US20040147543A1 - Aryl substituted imidazoquinolines - Google Patents

Aryl substituted imidazoquinolines Download PDF

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US20040147543A1
US20040147543A1 US10/739,787 US73978703A US2004147543A1 US 20040147543 A1 US20040147543 A1 US 20040147543A1 US 73978703 A US73978703 A US 73978703A US 2004147543 A1 US2004147543 A1 US 2004147543A1
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group consisting
selected
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alkyl
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David Hays
Shri Niwas
Tushar Kshirsagar
Tarun Ghosh
Shalley Gupta
Phillip Heppner
Bryon Merrill
Jason Bonk
Michael Danielson
John Gerster
Chad Haraldson
Sarah Johannessen
Maureen Kavanagh
Kyle Lindstrom
Ryan Prince
Matthew Radmer
Michael Rice
David Squire
Sarah Strong
Joshua Wurst
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3M Innovative Properties Co
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3M Innovative Properties Co
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems

Abstract

Aryl substituted imidazoquinoline compounds, pharmaceutical compositions containing the compounds, intermediates, and methods of use of these compounds as immunomodulators, for inducing or inhibiting cytokine biosynthesis in animals and in the treatment of diseases including viral, and neoplastic, are disclosed.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • The present application claims priority to U.S. Provisional Patent Application Serial No. 60/435,889, filed on Dec. 20, 2002, and to U.S. Provisional Patent Application Serial No. 60/516,331, filed on Oct. 31, 2003, which are both incorporated herein by reference in their entirety.[0001]
  • FIELD OF THE INVENTION
  • This invention relates to derivatives of imidazoquinoline compounds and to pharmaceutical compositions containing the compounds. A further aspect of this invention relates to the use of these compounds as immunomodulators, for inducing cytokine biosynthesis in animals and in the treatment of diseases including viral and neoplastic diseases. [0002]
  • BACKGROUND OF THE INVENTION
  • The first reliable report on the 1H-imidazo[4,5-c]quinoline ring system, Backman et al., [0003] J. Org. Chem., 15, 1278-1284 (1950) describes the synthesis of 1-(6-methoxy-8-quinolinyl)-2-methyl-1H-imidazo[4,5-c]quinoline for possible use as an antimalarial agent. Subsequently, syntheses of various substituted 1H-imidazo[4,5-c]quinolines were reported. For example, Jain et al., J. Med. Chem., 11, 87-92 (1968), synthesized the compound 1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline as a possible anticonvulsant and cardiovascular agent. Also, Baranov et al., Chem. Abs., 85, 94362 (1976), have reported several 2-oxoimidazo[4,5-c]quinolines, and Berenyi et al., J. Heterocyclic Chem., 18, 1537-1540 (1981), have reported certain 2-oxoimidazo[4,5-c]quinolines.
  • Certain 1H-imidazo[4,5-c]quinolin-4-amines and 1- and 2-substituted derivatives thereof were later found to be useful as antiviral agents, bronchodilators and immunomodulators. These are described in, inter alia, U.S. Pat. Nos. 4,689,338; 4,698,348; 4,929,624; 5,037,986; 5,268,376; 5,346,905; and 5,389,640. [0004]
  • There continues to be interest in the imidazoquinoline ring system and there is a continuing need for compounds that have the ability to modulate the immune response, by induction of cytokine biosynthesis or other mechanisms. [0005]
  • SUMMARY
  • The present invention provides a new class of compounds that are useful in inducing cytokine biosynthesis in animals. Such compounds are of the following Formula (I): [0006]
    Figure US20040147543A1-20040729-C00001
  • and more specifically of the following Formula (II): [0007]
    Figure US20040147543A1-20040729-C00002
  • wherein: R, n, R′, R″, R[0008] 1, R2, and R3 are as defined below.
  • The compounds of Formulas I and II are useful as immune response modifiers (IRMs) due to their ability to modulate cytokine biosynthesis (e.g., induce or inhibit the biosynthesis or production of one or more cytokines) and otherwise modulate the immune response when administered to animals. Compounds can be tested per the test procedures described in the Examples Section. Compounds can be tested for induction of cytokine biosynthesis by incubating human PBMC in a culture with the compound(s) at a concentration range of 30 to 0.014 μM and analyzing for interferon (a) or tumor necrosis factor (a) in the culture supernatant. Compounds can be tested for inhibition of cytokine biosynthesis by incubating mouse macrophage cell line Raw 264.7 in a culture with the compound(s) at a single concentration of, for example, 5 μM and analyzing for tumor necrosis factor (α) in the culture supernatant. Compounds can be further tested for dose response by running the test at several compound concentrations, for example, 0.03, 0.1, 0.3, 1, 3, 5, and 10 μM. The ability to modulate cytokine biosynthesis makes the compounds useful in the treatment of a variety of conditions such as viral diseases, neoplastic diseases, and autoimmune diseases that are responsive to such changes in the immune response. [0009]
  • In another aspect, the present invention provides pharmaceutical compositions containing the immune response modifier compounds, and methods of modulating (e.g., inducing or inhibiting) cytokine biosynthesis in an animal, treating a viral disease in an animal, and treating a neoplastic disease in an animal, by administering an effective amount of one or more compounds of Formula I (and more specifically, of Formula II) and/or pharmaceutically acceptable salts thereof to the animal. [0010]
  • In another aspect, the invention provides methods of synthesizing compounds of Formulas I and II and intermediates useful in the synthesis of these compounds. [0011]
  • As used herein, “a,” “an,” “the,” “at least one,” and “one or more” are used interchangeably. [0012]
  • The terms “comprising” and variations thereof do not have a limiting meaning where these terms appear in the description and claims. [0013]
  • The above summary of the present invention is not intended to describe each disclosed embodiment or every implementation of the present invention. The description that follows more particularly exemplifies illustrative embodiments. Guidance is also provided herein through lists of examples, which can be used in various combinations. In each instance, the recited list serves only as a representative group and should not be interpreted as an exclusive list. [0014]
  • DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS OF THE INVENTION
  • The present invention provides compounds of the following Formula (I): [0015]
    Figure US20040147543A1-20040729-C00003
  • wherein: [0016]
  • R is selected from the group consisting of alkyl, alkoxy, hydroxy, and trifluoromethyl; [0017]
  • n is 0 or 1; [0018]
  • R′ and R″ are independently selected from the group consisting of hydrogen and non-interfering substitutents; [0019]
  • R[0020] 3 is selected from the group consisting of:
  • —Z—Ar, [0021]
  • —Z—Ar′—Y—R[0022] 4,
  • —Z—Ar′—X—Y—R[0023] 4,
  • —Z—Ar′—R[0024] 5, and
  • —Z—Ar′—X—R[0025] 5;
  • Ar is selected from the group consisting of aryl and heteroaryl both of which can be unsubstituted or can be substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkoxy, methylenedioxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, amino, alkylamino, and dialkylamino; [0026]
  • Ar′ is selected from the group consisting of arylene and heteroarylene both of which can be unsubstituted or can be substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, amino, alkylamino, and dialkylamino; [0027]
  • X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more —O— groups; [0028]
  • Y is selected from the group consisting of: [0029]
    Figure US20040147543A1-20040729-C00004
  • Z is selected from the group consisting of a bond, alkylene, alkenylene, and alkynylene; [0030]
  • R[0031] 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;
  • R[0032] 5 is selected from the group consisting of:
    Figure US20040147543A1-20040729-C00005
  • R[0033] 6 is selected from the group consisting of ═O and ═S;
  • each R[0034] 7 is independently C2-7 alkylene;
  • R[0035] 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and arylalkylenyl;
  • R[0036] 9 is selected from the group consisting of hydrogen and alkyl;
  • each R[0037] 10 is independently C3-8 alkylene;
  • A is selected from the group consisting of —O—, —C(O)—, —S(O)[0038] 0-2—, —CH2—, and —N(R4)—;
  • Q is selected from the group consisting of a bond, —C(R[0039] 6)—, —C(R6)—C(R6), —S(O)2—, —C(R6)—N(R8)—W—, —S(O)2—N(R8)—, —C(R6)—O—, and —C(R6)—N(OR9)—;
  • V is selected from the group consisting of —C(R[0040] 6)—, —O—C(R6)—, —N(R8)—C(R6)—, and —S(O)2—;
  • W is selected from the group consisting of a bond, —C(O)—, and —S(O)[0041] 2—; and
  • a and b are independently integers from 1 to 6 with the proviso that a +b is ≦7; [0042]
  • or a pharmaceutically acceptable salt thereof. [0043]
  • For certain embodiments of Formula I, n is 0 and —Z— is a bond. For certain embodiments of Formula I, R[0044] 3 is —Z—Ar, and for certain other embodiments, R3 is
  • —Z—Ar′—Y—R[0045] 4 or —Z—Ar′—X—Y—R4.
  • For some embodiments of Formula I, R′ is selected from the group consisting of: [0046]
  • —R[0047] 4,
  • —X—R[0048] 4,
  • —X—Y—R[0049] 4,
  • —X—Y—X—Y—R[0050] 4, and
  • —X—R[0051] 5;
  • wherein each X is independently selected, each Y is independently selected, each R[0052] 4 is independently selected, and each R5 is independently selected.
  • For some embodiments of Formula I, R″ is selected from the group consisting of: [0053]
  • —R[0054] 4,
  • —X—R[0055] 4,
  • —X—Y—R[0056] 4, and
  • —X—R[0057] 5;
  • wherein each X is independently selected, each Y is independently selected, each R[0058] 4 is independently selected, and each R5 is independently selected.
  • The present invention also provides compounds of the following Formula (II): [0059]
    Figure US20040147543A1-20040729-C00006
  • wherein: [0060]
  • R is selected from the group consisting of alkyl, alkoxy, hydroxy, and trifluoromethyl; [0061]
  • n is 0 or 1; [0062]
  • R[0063] 1 is selected from the group consisting of:
  • —R[0064] 4,
  • —X—R[0065] 4,
  • —X—Y—R[0066] 4,
  • —X-Y—X—Y—R[0067] 4, and
  • —X—R[0068] 5;
  • R[0069] 2 is selected from the group consisting of:
  • —R[0070] 4,
  • —X—R[0071] 4,
  • —X—Y—R[0072] 4, and
  • —X—R[0073] 5;
  • R[0074] 3 is selected from the group consisting of:
  • —Z—Ar, [0075]
  • —Z—Ar′—Y—R[0076] 4,
  • —Z—Ar′—X—Y—R[0077] 4,
  • —Z—Ar′—R[0078] 5, and
  • —Z—Ar′—X—R[0079] 5;
  • Ar is selected from the group consisting of aryl and heteroaryl both of which can be unsubstituted or can be substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkoxy, methylenedioxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, amino, alkylamino, and dialkylamino; [0080]
  • Ar′ is selected from the group consisting of arylene and heteroarylene both of which can be unsubstituted or can be substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, amino, alkylamino, and dialkylamino; [0081]
  • each X is independently selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more -0- groups; [0082]
  • each Y is independently selected from the group consisting of: [0083]
    Figure US20040147543A1-20040729-C00007
  • Z is selected from the group consisting of a bond, alkylene, alkenylene, and alkynylene; [0084]
  • each R[0085] 4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;
  • each R[0086] 5 is independently selected from the group consisting of:
    Figure US20040147543A1-20040729-C00008
  • each R[0087] 6 is independently selected from the group consisting of ═O and ═S;
  • each R[0088] 7 is independently C2-7 alkylene;
  • R[0089] 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and arylalkylenyl;
  • R[0090] 9 is selected from the group consisting of hydrogen and alkyl;
  • each R[0091] 10 is independently C3-8 alkylene;
  • A is selected from the group consisting of —O—, —C(O)—, —S(O)[0092] 0-2—, —CH2—, and —N(R4)—;
  • Q is selected from the group consisting of a bond, —C(R[0093] 6)—, —C(R6)—C(R6), —S(O)2—, —C(R6)—N(R8)—W—, —S(O)2—N(R8)—, —C(R6)—O—, and —C(R6)—N(OR9)—;
  • V is selected from the group consisting of —C(R[0094] 6)—, —O—C(R6)—, —N(R8)—C(R6)—, and —S(O)2—;
  • W is selected from the group consisting of a bond, —C(O)—, and —S(O)[0095] 2—; and
  • a and b are independently integers from 1 to 6 with the proviso that a +b is ≦7; [0096]
  • or a pharmaceutically acceptable salt thereof. [0097]
  • In some embodiments of Formula II, R[0098] 1 is selected from the group consisting of alkyl, arylalkylenyl, aryloxyalkylenyl, hydroxyalkyl, alkylsulfonylalkylenyl, —X—Y—R4, and —X—R5; wherein X is alkylene; Y is selected from the group consisting of —N(R8)—C(O)—, —N(R8)—S(O)2—, —N(R8)—C(O)—N(R8)—,
  • and [0099]
    Figure US20040147543A1-20040729-C00009
  • R[0100] 4is selected from the group consisting of alkyl, aryl, and heteroaryl; and R5 is selected from the group consisting of
    Figure US20040147543A1-20040729-C00010
  • In some embodiments of Formula II, R[0101] 2 is selected from the group consisting of hydrogen, alkyl, and alkoxyalkylenyl.
  • For some embodiments of Formula II, n is 0 and —Z— is a bond. For some embodiments of Formula II, R[0102] 3 is —Z—Ar, and for certain of these embodiments, R3 is selected from the group consisting of phenyl, pyridyl, pyrrolyl, thienyl, and furyl; each of which can be unsubstituted or can be substituted by one or more substituents selected from the group consisting of halogen, alkyl, hydroxy, hydroxyalkyl, alkoxy, carboxy, and cyano.
  • For some embodiments of Formula II, R[0103] 3 is —Z—Ar′—Y—R4, —Z—Ar′—X—Y—R4, or —Z—Ar′—R5, and for certain of these embodiments, Ar′ is phenyl or pyridyl;
  • Y is selected from the group consisting of: [0104]
  • —S(O)[0105] 0-2
  • —C(O)—, [0106]
  • —N(R[0107] 8)—Q—,
  • —C(R[0108] 6)—N(R8)—, and
  • —C(R[0109] 6)—N(OR9)—;
  • wherein Q is selected from the group consisting of a bond, —C(O)—, and —S(O)[0110] 2—; R8 is selected from the group consisting of hydrogen, C1-4 alkyl, and alkoxyalkylenyl;
  • X is C[0111] 1-4 alkylene;
  • R[0112] 4 is selected from the group consisting of alkyl, aryl, heteroaryl, and heterocyclyl; and
  • R[0113] 5 is
    Figure US20040147543A1-20040729-C00011
  • The present invention also provides compounds of the following Formula (IIa): [0114]
    Figure US20040147543A1-20040729-C00012
  • wherein: [0115]
  • R is selected from the group consisting of alkyl, alkoxy, hydroxy, and trifluoromethyl; [0116]
  • n is 0 or 1; [0117]
  • R[0118] 1 is selected from the group consisting of:
  • —R[0119] 4,
  • —X—R[0120] 4,
  • —X—Y—R[0121] 4,
  • —X—Y—X—Y—R[0122] 4, and
  • —X—R[0123] 5;
  • R[0124] 2 is selected from the group consisting of:
  • —R[0125] 4,
  • —X—R[0126] 4,
  • —X—Y—R[0127] 4, and
  • —X—R[0128] 5;
  • R[0129] 3 is selected from the group consisting of:
  • —Z—Ar and [0130]
  • —Z—Ar′—Y—R[0131] 4;
  • each X is independently selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted by arylene, heteroarylene or heterocyclylene or by one or more —O— groups; [0132]
  • each Y is independently selected from the group consisting of: [0133]
    Figure US20040147543A1-20040729-C00013
  • Z is selected from the group consisting of a bond, alkylene, alkenylene, and alkynylene; [0134]
  • Ar is selected from the group consisting of aryl and heteroaryl both of which can be unsubstituted or can be substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, amino, alkylamino, and dialkylamino; [0135]
  • Ar′ is selected from the group consisting of arylene and heteroarylene both of which can be unsubstituted or can be substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, amino, alkylamino, and dialkylamino; [0136]
  • each R[0137] 4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, amino, alkylamino, dialkylamino, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;
  • each R[0138] 5 is independently selected from the group consisting of:
    Figure US20040147543A1-20040729-C00014
  • R[0139] 6 is selected from the group consisting of ═O and ═S;
  • R[0140] 7 is C2-7 alkylene;
  • each R[0141] 8 present is independently selected from the group consisting of hydrogen, alkyl, and arylalkyl;
  • R[0142] 9 is selected from the group consisting of hydrogen and alkyl;
  • A is selected from the group consisting of —O—, —S(O)[0143] 0-2—, —NR4—, and —CH2—;
  • Q is selected from the group consisting of—CR[0144] 6—, —SO2—, —CR6—NR8—W—, —SO2—NR8—, —CR6—O—, and —CR6—N(OR9)—;
  • V is selected from the group consisting of —CR[0145] 6—, —O—CR6—, and —NR8—CR6—;
  • W is selected from the group consisting of a bond, —C(O)—, and —SO[0146] 2—; and
  • a and b are independently integers from 1 to 6 with the proviso that a +b is ≦7; [0147]
  • or a pharmaceutically acceptable salt thereof. [0148]
  • For certain embodiments of Formula Ia, n is 0 and the R[0149] 1, R2, and R3 groups are defined as follows: R1 is R4 or —X—Y—R4, R1 is alkyl or hydroxyalkyl, —X— is C2-6 alkylene, and —Y— is —S(O)0-2— or —NR8—Q—; R2 is R4 or R2 is alkyl or alkoxyalkyl; R3 is —Z—Ar, —Z— is a bond, —Ar is unsubstituted aryl or heteroaryl, and more particularly —Ar is phenyl, thienyl or pyridyl; and R3 is attached at the 7-position or 8-position per the following numbering scheme.
    Figure US20040147543A1-20040729-C00015
  • The present invention also provides compounds of the following Formula (III), which include a sulfonamide functional group: [0150]
    Figure US20040147543A1-20040729-C00016
  • wherein: [0151]
  • R[0152] 2 is selected from the group consisting of:
  • —R[0153] 4,
  • —X—R[0154] 4,
  • —X—Y—R[0155] 4, and
  • —X—R[0156] 5;
  • R[0157] 3 is selected from the group consisting of:
  • —Z—Ar, [0158]
  • —Z—Ar′—Y—R[0159] 4,
  • —Z—Ar′—X—Y—R[0160] 4,
  • —Z—Ar′—R[0161] 5, and
  • —Z—Ar′—X—R[0162] 5;
  • Ar is selected from the group consisting of aryl and heteroaryl both of which can be unsubstituted or can be substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkoxy, methylenedioxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, amino, alkylamino, and dialkylamino; [0163]
  • Ar′ is selected from the group consisting of arylene and heteroarylene both of which can be unsubstituted or can be substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, amino, alkylamino, and dialkylamino; [0164]
  • each X is independently selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more —O— groups; [0165]
  • X′ is C[0166] 2-8 alkylene;
  • each Y is independently selected from the group consisting of: [0167]
    Figure US20040147543A1-20040729-C00017
  • Z is selected from the group consisting of a bond, alkylene, alkenylene, and alkynylene; [0168]
  • each R[0169] 4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;
  • each R[0170] 5 is independently selected from the group consisting of:
    Figure US20040147543A1-20040729-C00018
  • each R[0171] 6 is independently selected from the group consisting of ═O and ═S;
  • each R[0172] 7 is independently C2-7 alkylene;
  • R[0173] 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and arylalkylenyl;
  • R[0174] 9 is selected from the group consisting of hydrogen and alkyl;
  • each R[0175] 10 is independently C3-8 alkylene;
  • A is selected from the group consisting of —O—, —C(O)—, —S(O)[0176] 0-2—, —CH2—, and —N(R4)—;
  • Q is selected from the group consisting of a bond, —C(R[0177] 6)—, —C(R6)—C(R6), —S(O)2—, —C(R6)—N(R8)—W—, —S(O)2—N(R8)—, —C(R6)—O—, and —C(R6)—N(OR9)—;
  • V is selected from the group consisting of—C(R[0178] 6)—, —O—C(R6)—, —N(R8)—C(R6)—, and —S(O)2—;
  • W is selected from the group consisting of a bond, —C(O)—, and —S(O)[0179] 2—; and
  • a and b are independently integers from 1 to 6 with the proviso that a +b is ≦7; [0180]
  • or a pharmaceutically acceptable salt thereof. [0181]
  • For certain embodiments of Formula III, X′ is —CH[0182] 2—C(CH3)2—.
  • For certain embodiments of Formula III, R[0183] 2 is selected from the group consisting of hydrogen, C1-4 alkyl, and C1-4 alkyl-O—C1-4 alkylenyl.
  • For certain embodiments of Formula III, R[0184] 4 is selected from the group consisting of alkyl, aryl, and heteroaryl.
  • For certain embodiments of Formula III, R[0185] 3 is phenyl or pyridyl, either of which can be unsubstituted or can be substituted by one or more substituents selected from the group consisting of halogen, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkylsulfonylamino, arylsulfonylamino, alkylcarbonylanino, arylcarbonylamino, alkylsulfonylaminoalkylenyl, arylsulfonylaminoalkylenyl, alkylcarbonylaminoalkylenyl, and arylcarbonylaminoalkylenyl.
  • The present invention also provides compounds of the following Formula (IV), which include an amide functional group: [0186]
    Figure US20040147543A1-20040729-C00019
  • wherein R[0187] 2, R3, R4, and X′ are the same as that for Formula III listed above; or a pharmaceutically acceptable salt thereof.
  • For certain embodiments of Formula IV, X′ is —CH[0188] 2—C(CH3)2—.
  • For certain embodiments of Formula IV, R[0189] 2 is selected from the group consisting of hydrogen, C1-4 alkyl, and C1-4 alkyl-O—C1-4 alkylenyl.
  • For certain embodiments of Formula IV, R[0190] 4 is selected from the group consisting of alkyl, aryl, and heteroaryl.
  • For certain embodiments of Formula IV, R[0191] 3 is phenyl or pyridyl, either of which can be unsubstituted or can be substituted by one or more substituents selected from the group consisting of halogen, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkylsulfonylamino, arylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylaminoalkylenyl, arylsulfonylaminoalkylenyl, alkylcarbonylaminoalkylenyl, and arylcarbonylaminoalkylenyl.
  • The present invention also provides compounds of the following Formula (V), which include a urea functional group: [0192]
    Figure US20040147543A1-20040729-C00020
  • wherein R[0193] 2, R3, R4, and X′ are the same as that for Formula III listed above; or a pharmaceutically acceptable salt thereof.
  • For certain embodiments of Formula V, X′ is —CH[0194] 2—C(CH3)2—.
  • For certain embodiments of Formula V, R[0195] 2 is selected from the group consisting of hydrogen, C1-4 alkyl, and C1-4 alkyl-O—C1-4 alkylenyl.
  • For certain embodiments of Formula V, R[0196] 4 is selected from the group consisting of alkyl, aryl, and heteroaryl.
  • For certain embodiments of Formula V, R[0197] 3 is phenyl or pyridyl, either of which can be unsubstituted or can be substituted by one or more substituents selected from the group consisting of halogen, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkylsulfonylamino, arylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylaminoalkylenyl, arylsulfonylaminoalkylenyl, alkylcarbonylaminoalkylenyl, and arylcarbonylaminoalkylenyl.
  • The present invention also provides compounds of the following Formula (VI), which include a piperidine moiety: [0198]
    Figure US20040147543A1-20040729-C00021
  • wherein R[0199] 2, R3, R4, Q, and X′ are the same as that for Formula III listed above; or a pharmaceutically acceptable salt thereof.
  • For certain embodiments of Formula VI, Q is selected from the group consisting of —C(O)—, —S(O)[0200] 2—, and —C(O)—NH—.
  • For certain embodiments of Formula VI, R[0201] 2 is selected from the group consisting of hydrogen, C1-4 alkyl, and C1-4 alkyl-O—C1-4 alkylenyl.
  • For certain embodiments of Formula VI, R[0202] 4 is selected from the group consisting of alkyl, aryl, and heteroaryl.
  • For certain embodiments of Formula VI, R[0203] 3 is phenyl or pyridyl, either of which can be unsubstituted or can be substituted by one or more substituents selected from the group consisting of halogen, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkylsulfonylamino, arylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylaminoalkylenyl, arylsulfonylaminoalkylenyl, alkylcarbonylaminoalkylenyl, and arylcarbonylaminoalkylenyl.
  • The present invention also provides compounds of the following Formula (VII): [0204]
    Figure US20040147543A1-20040729-C00022
  • wherein R[0205] 2, R3, R5, and X′ are the same as that for Formula III listed above; or a pharmaceutically acceptable salt thereof.
  • For certain embodiments of Formula VII, R[0206] 2 is selected from the group consisting of hydrogen, C1-4 alkyl, and C1-4 alkyl-O—C1-4 alkylenyl.
  • For certain embodiments of Formula VII, R[0207] 3 is phenyl or pyridyl, either of which can be unsubstituted or can be substituted by one or more substituents selected from the group consisting of halogen, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkylsulfonylamino, arylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylaminoalkylenyl, arylsulfonylaminoalkylenyl, alkylcarbonylaminoalkylenyl, and arylcarbonylaminoalkylenyl.
  • For certain embodiments of Formula VII, R[0208] 5 is selected from the group consisting of:
    Figure US20040147543A1-20040729-C00023
  • The present invention also provides compounds of the following Formula (VIII): [0209]
    Figure US20040147543A1-20040729-C00024
  • wherein R[0210] 2, R3, and R4 are the same as that for Formula III listed above; or a pharmaceutically acceptable salt thereof.
  • For certain embodiments of Formula VIII, R[0211] 2 is selected from the group consisting of hydrogen, C1-4 alkyl, and C1-4 alkyl-O—C1-4 alkylenyl.
  • For certain embodiments of Formula VIII, R[0212] 3 is phenyl or pyridyl, either of which can be unsubstituted or can be substituted by one or more substituents selected from the group consisting of halogen, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkylsulfonylamino, arylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylaminoalkylenyl, arylsulfonylaminoalkylenyl, alkylcarbonylaminoalkylenyl, and arylcarbonylaminoalkylenyl.
  • For certain embodiments of Formula VIII, R[0213] 4 is selected from the group consisting of C1-6 alkyl, C1-6 hydroxyalkyl, C1-4 alkyl-O—C1-4 alkylenyl, and aryl-O—C1-4 alkylenyl.
  • For certain embodiments of Formula VIII, R[0214] 4 is selected from the group consisting of 2-methylpropyl, 2-hydroxy-2-methylpropyl, 3-methoxypropyl, and phenoxyethyl.
  • The present invention also provides a compound of the following Formula (XLVI): [0215]
    Figure US20040147543A1-20040729-C00025
  • wherein: [0216]
  • R[0217] 1 is selected from the group consisting of:
  • —R[0218] 4,
  • —X—R[0219] 4,
  • —X—Y—R[0220] 4,
  • —X-Y—X—Y—R[0221] 4, and
  • —X—R[0222] 5;
  • R[0223] 2 is selected from the group consisting of:
  • —R[0224] 4,
  • —X—R[0225] 4,
  • —X—Y—R[0226] 4, and
  • —X—R[0227] 5;
  • Ar′ is selected from the group consisting of arylene and heteroarylene both of which can be unsubstituted or can be substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, amino, alkylamino, and dialkylamino; [0228]
  • each X is independently selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more —O— groups; [0229]
  • each Y is independently selected from the group consisting of: [0230]
    Figure US20040147543A1-20040729-C00026
  • each Z is independently selected from the group consisting of a bond, alkylene, alkenylene, and alkynylene; [0231]
  • each R[0232] 4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkytheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;
  • each R[0233] 5 is independently selected from the group consisting of:
    Figure US20040147543A1-20040729-C00027
  • each R[0234] 6 is independently selected from the group consisting of ═O and ═S;
  • each R[0235] 7 is independently C2-7 alkylene;
  • R[0236] 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and arylalkylenyl;
  • R[0237] 9 is selected from the group consisting of hydrogen and alkyl;
  • each R[0238] 10 is independently C3-8 alkylene;
  • A is selected from the group consisting of —O—, —C(O)—, —S(O)[0239] 0-2—, —CH2—, and —N(R4)—;
  • Q is selected from the group consisting of a bond, —C(R[0240] 6)—, —C(R6)—C(R6), —S(O)2—, —C(R6)—N(R8)—W—, —S(O)2—N(R8)—, —C(R6)—O—, and —C(R6)—N(OR9)—;
  • V is selected from the group consisting of —C(R[0241] 6)—, —O—C(R6)—, —N(R8)—C(R6)—, and —S(O)2—;
  • W is selected from the group consisting of a bond, —C(O)—, and —S(O)[0242] 2—; and
  • a and b are independently integers from 1 to 6 with the proviso that a +b is ≦7; [0243]
  • or a pharmaceutically acceptable salt thereof. [0244]
  • For certain embodiments of Formula XLVI, Z is a bond and Ar′ is phenylene. For certain embodiments of Formula XLVI, R[0245] 1 is selected from the group consisting of alkyl, hydroxyalkyl, and —X—Y—R4 wherein X is alkylene, Y is selected from the group consisting of —N(R8)—C(O)—, —N(R8)—S(O)2—, and —N(R8)—C(O)—N(R8)—, and R4 is alkyl. For certain embodiments of Formula XLVI, R2 is selected from the group consisting of hydrogen, alkyl, and alkoxyalkylenyl.
  • The present invention also provides compounds of the following Formulas XLVII and XLVIII, which are intermediates in the preparation of certain compounds of the present invention: [0246]
    Figure US20040147543A1-20040729-C00028
  • wherein: [0247]
  • R is selected from the group consisting of alkyl, alkoxy, hydroxy, and trifluoromethyl; [0248]
  • n is 0 or 1; [0249]
  • R[0250] 1 is selected from the group consisting of:
  • —R[0251] 4,
  • —X—R[0252] 4,
  • —X—Y—R[0253] 4,
  • —X—Y—X—Y—R[0254] 4, and
  • —X—R[0255] 5;
  • R[0256] 2 is selected from the group consisting of:
  • —R[0257] 4,
  • —X—R[0258] 4,
  • —X—Y—R[0259] 4, and
  • —X—R[0260] 5;
  • R[0261] 3 is selected from the group consisting of:
  • —Z—Ar, [0262]
  • —Z—Ar′—Y—R[0263] 4,
  • —Z—Ar′—X—Y—R[0264] 4,
  • —Z—Ar′—R[0265] 5, and
  • —Z—Ar′—X—R[0266] 5;
  • Ar is selected from the group consisting of aryl and heteroaryl both of which can be unsubstituted or can be substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkoxy, methylenedioxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, amino, alkylamino, and dialkylamino; [0267]
  • Ar′ is selected from the group consisting of arylene and heteroarylene both of which can be unsubstituted or can be substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, amino, alkylamino, and dialkylamino; [0268]
  • each X is independently selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more —O— groups; [0269]
  • each Y is independently selected from the group consisting of: [0270]
    Figure US20040147543A1-20040729-C00029
  • Z is selected from the group consisting of a bond, alkylene, alkenylene, and alkynylene; [0271]
  • each R[0272] 4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;
  • each R[0273] 5 is independently selected from the group consisting of:
    Figure US20040147543A1-20040729-C00030
  • each R[0274] 6 is independently selected from the group consisting of ═O and ═S;
  • each R[0275] 7 is independently C2-7 alkylene;
  • R[0276] 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and arylalkylenyl;
  • R[0277] 9 is selected from the group consisting of hydrogen and alkyl;
  • each R[0278] 10 is independently C3-8 alkylene;
  • A is selected from the group consisting of —O—, —C(O)—, —S(O)[0279] 0-2—, —CH2—, and —N(R4)—;
  • Q is selected from the group consisting of a bond, —C(R[0280] 6)—, —C(R6)—C(R6), —S(O)2—, —C(R6)—N(R8)—W—, —S(O)2—N(R8)—, —C(R6)—O—, and —C(R6)—N(OR9)—;
  • V is selected from the group consisting of —C(R[0281] 6)—, —O—C(R6)—, —N(R8)—C(R6)—, and —S(O)2—;
  • W is selected from the group consisting of a bond, —C(O)—, and —S(O)[0282] 2—; and
  • a and b are independently integers from 1 to 6 with the proviso that a +b is ≦7; [0283]
  • or a pharmaceutically acceptable salt thereof. [0284]
  • Herein, “non-interfering” means that the ability of the compound or salt to modulate (e.g., induce or inhibit) the biosynthesis of one or more cytokines is not destroyed by the non-interfering substitutent. Illustrative non-interfering R′ groups include those described above for R[0285] 1 in Formula II. Illustrative non-interfering R″ groups include those described above for R2 in Formula II.
  • As used herein, the terms “alkyl,” “alkenyl,” “alkynyl” and the prefix “alk-” are inclusive of both straight chain and branched chain groups and of cyclic groups, i.e. cycloalkyl and cycloalkenyl. Unless otherwise specified, these groups contain from 1 to 20 carbon atoms, with alkenyl groups containing from 2 to 20 carbon atoms, and alkynyl groups containing from 2 to 20 carbon atoms. In some embodiments, these groups have a total of up to 10 carbon atoms, up to 8 carbon atoms, up to 6 carbon atoms, or up to 4 carbon atoms. Cyclic groups can be monocyclic or polycyclic and preferably have from 3 to 10 ring carbon atoms. Exemplary cyclic groups include cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, adamantyl, and substituted and unsubstituted bornyl, norbornyl, and norbornenyl. [0286]
  • Unless otherwise specified, “alkylene,” “alkenylene,” and “alkynylene” are the divalent forms of the “alkyl,” “alkenyl,” and “alkynyl” groups defined above. Likewise, “alkylenyl,” “alkenylenyl,” and “alkynylenyl” are the divalent forms of the “alkyl,” “alkenyl,” and “alkynyl” groups defined above. For example, an arylalkylenyl group comprises an alkylene moiety to which an aryl group is attached. [0287]
  • The term “haloalkyl” is inclusive of groups that are substituted by one or more halogen atoms, including perfluorinated groups. This is also true of other groups that include the prefix “halo-”. Examples of suitable haloalkyl groups are chloromethyl, trifluoromethyl, and the like. [0288]
  • The term “aryl” as used herein includes carbocyclic aromatic rings or ring systems. Examples of aryl groups include phenyl, naphthyl, biphenyl, fluorenyl and indenyl. [0289]
  • The term “heteroatom” refers to the atoms O, S, or N. [0290]
  • The term “heteroaryl” includes aromatic rings or ring systems that contain at least one ring heteroatom (e.g., O, S, N). Suitable heteroaryl groups include furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl, benzimidazolyl, quinoxalinyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl, purinyl, quinazolinyl, pyrazinyl, 1-oxidopyridyl, pyridazinyl, triazinyl, tetrazinyl, oxadiazolyl, thiadiazolyl, and so on. [0291]
  • The term “heterocyclyl” includes non-aromatic rings or ring systems that contain at least one ring heteroatom (e.g., O, S, N) and includes all of the fully saturated and partially unsaturated derivatives of the above mentioned heteroaryl groups. Exemplary heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, imidazolidinyl, isothiazolidinyl, tetrahydropyranyl, quinuclidinyl, homopiperidinyl, homopiperazinyl, and the like. [0292]
  • The terms “arylene,” “heteroarylene,” and “heterocyclylene” are the divalent forms of the “aryl,” “heteroaryl,” and “heterocyclyl” groups defined above. Likewise, “arylenyl,” “heteroarylenyl,” and “heterocyclylenyl” are the divalent forms of the “aryl,” “heteroaryl,” and “heterocyclyl” groups defined above. For example, an alkylarylenyl group comprises an arylene moiety to which an alkyl group is attached. [0293]
  • When a group is present more that once in a Formula I-VIII or XLVI-XLVIII described herein, each group is independently selected, whether specifically stated or not. For example, when more than one Y group is present in a Formula, each Y group is independently selected. Furthermore, subgroups contained within these groups are also independently selected. For example, when each Y group contains an R[0294] 6, each R6 is also independently selected.
  • The invention is inclusive of the compounds and salts thereof, described herein in any of their pharmaceutically acceptable forms, including isomers (e.g., diastereomers and enantiomers), solvates, polymorphs, and the like. In particular, if a compound is optically active, the invention specifically includes each of the compound's enantiomers as well as racemic mixtures of the enantiomers. [0295]
  • In some embodiments, compounds of Formulas I-VIII and XLVI induce the biosynthesis of one or more cytokines. [0296]
  • In some embodiments, compounds of Formulas I-VIII and XLVI inhibit the biosynthesis of one or more cytokines. [0297]
  • Preparation of the Compounds [0298]
  • Compounds of the invention can be prepared using known palladium catalyzed coupling reactions such as Suzuki coupling, Stille coupling, Sonogashira coupling, and the Heck reaction. [0299]
  • Suzuki coupling is used in Reaction Scheme I where R[0300] 1, R2, and R are as defined above, R3a is —Za—Ar, —Za—Ar′—Y—R4, or —Za—Ar′—X—Y—R4 where Za is a bond, alkylene or alkenylene, and Hal is bromo, chloro or iodo.
  • In Reaction Scheme I a halogen substituted imidazoquinoline of Formula IX is coupled with a boronic acid of Formula X to provide an imidazoquinoline of Formula XI which is a subgenus of Formula II. A compound of Formula IX is combined with a boronic acid of Formula X in the presence of palladium (II) acetate, triphenylphosphine and a base such as sodium carbonate in a suitable solvent such as n-propanol. The reaction can be carried out at an elevated temperature (e.g., 80-100° C). [0301]
    Figure US20040147543A1-20040729-C00031
  • Many compounds of Formula IX are known. See, for example, U.S. Pat. Nos. 4,689,338; 4,929,624; 5,268,376; 5,346,905; 5,389,640; 5,756,747; 6,331,539; and 6,451,810; PCT Publications WO 00/76518; WO 02/46188, WO 02/46189; WO 02/46190; WO 02/46191; WO 02/46192; and WO 02/46193; European Patent Application 1 104 764; and Japanese Patent Application 9- 255926. Others can be readily prepared using known synthetic methods. See, for example, U.S. Patent Nos. 4,988,815; 5,175,296; 5,367,076; 5,395,937; and 5,741,908. [0302]
  • Many boronic acids of Formula X are commercially available; others can be readily prepared using known synthetic methods. See, for example, Li, W. et al, J Org. Chem., 67, 5394-5397 (2002). The Suzuki coupling reaction can also be carried out using boronic acid esters of Formula R[0303] 3a-B(O-alkyl)2 and anhydrides of boronic acids of Formula X.
  • Compounds of the invention where Z is alkynylene can be prepared using Stille coupling to couple a halogen substituted imidazoquinoline of Formula IX with a terminal alkyne of the formula —C≡C—Ar. [0304]
  • Compounds of the invention can be prepared according to Reaction Scheme II wherein R[0305] b is selected from alkyl, and alkoxy; R1b and R2b are subsets of R1 and R2 as defined above, which subsets do not include those substituents which one skilled in the art would recognize as being susceptible to oxidation in step (9), examples include substituents containing an —S— or a heteroaryl group; R3b is aryl which may be unsubstituted or substituted by one or more substituents independently selected from alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heterocyclyl, heterocyclylalkyl, amino, alkylamino, and dialkylamino; and n is 0 or 1.
  • In step (1) of Reaction Scheme II a bromoaniline of Formula XII is coupled with a boronic acid of formula R[0306] 3b—B(OH)2, an anhydride thereof, or a boronic acid ester of Formula R3a-B(O-alkyl)2 using the method described in Reaction Scheme I to provide an aryl substituted aniline of Formula XIII. Many bromoanilines of Formula XII are commercially available; others can be readily prepared using known synthetic methods.
  • In step (2) of Reaction Scheme II an aryl substituted aniline of Formula XIII is reacted with a mixture of triethyl orthoformate and Meldrum's Acid (2,2-dimethyl-1,3-dioxane-4,6-dione) at an elevated temperature (50-55° C.) to provide a compound of Formula XIV. [0307]
  • In step (3) of Reaction Scheme II a quinolin-4-ol of Formula XV is prepared by thermolysis of a compound of Formula XIV. The reaction can be carried out by heating (approximately 215° C.) a solution of the compound of Formula XIV in a heat transfer fluid. [0308]
  • In step (4) of Reaction Scheme II a quinolin-4-ol of Formula XV is nitrated using conventional nitration methods to provide a 3-nitroquinolin-4-ol of Formula XVI. The reaction can be carried out by combining the compound of Formula XV with nitric acid in a suitable solvent such as propionic acid at an elevated temperature (approximately 130° C.). [0309]
  • In step (5) of Reaction Scheme II a 3-nitroquinolin-4-ol of Formula XVI is chlorinated using conventional chlorinating methods to provide a 4-chloro-3-nitroquinoline of Formula XVII. The reaction can be carried out by combining the compound of Formula XVI with phosphorous oxychloride in a suitable solvent such as toluene. The reaction can be carried out at ambient temperature. [0310]
  • In step (6) of Reaction Scheme II a 4-chloro-3-nitroquinoline of Formula XVII is reacted with an amine of Formula R[0311] 1b—NH2 to provide a 3-nitroquinolin-4-amine of Formula XVIII. The reaction can be carried out by adding the amine to a solution of the compound of Formula XVII in a suitable solvent such as N,N-dimethylformamide (DMF) in the presence of a tertiary amine such as triethylamine. The addition can be carried out at a reduced temperature (0° C.) or at ambient temperature.
  • In step (7) of Reaction Scheme II a 3-nitroquinolin-4-amine of Formula XVIII is reduced to provide a quinoline-3,4-diamine of Formula XIX. The reaction can be carried out using a conventional heterogeneous hydrogenation catalyst such as platinum on carbon or palladium on carbon. The reaction can conveniently be carried out on a Parr apparatus in a suitable solvent such as toluene, isopropanol, or mixtures thereof. [0312]
  • Alternatively the reduction in step (7) can be carried out using sodium dithionite. A solution or suspension of the compound of Formula XVIII in a suitable solvent such as ethanol or isopropanol is treated with an aqueous solution of sodium dithionite. The reaction can be carried out at an elevated temperature (reflux) or at ambient temperature. [0313]
  • In step (8) of Reaction Scheme II a quinoline-3,4-diamine of Formula XIX is reacted with a carboxylic acid or an equivalent thereof to provide a 1H-imidazo[4,5-c]quinoline of Formula XX. Suitable equivalents to carboxylic acid include orthoesters, and 1,1-dialkoxyalkyl alkanoates. The carboxylic acid or equivalent is selected such that it will provide the desired R[0314] 2b substituent in a compound of Formula XX. For example, triethyl orthoformate will provide a compound where R2b is hydrogen and trimethyl orthovalerate will provide a compound where R2b is butyl. The reaction can be run in the absence of solvent or in an inert solvent such as toluene. The reaction is run with sufficient heating to drive off any alcohol or water formed as a byproduct of the reaction. Optionally a catalyst such as pyridine hydrochloride can be included.
  • Alternatively, step (8) can be carried out by (i) reacting a compound of Formula XIX with an acyl halide of formula R[0315] 2bC(O)Cl or R2bC(O)Br and then (ii) cyclizing. In part (i) the acyl halide is added to a solution of a compound of Formula XIX in an inert solvent such as acetonitrile, pyridine or dichloromethane. The reaction can be carried out at ambient temperature. Optionally a catalyst such as pyridine hydrochloride can be included. In part (ii) the product of part (i) is heated in pyridine. If step (i) is run in pyridine, then the two steps can be combined into a single step.
  • In step (9) of Reaction Scheme II a 1H-imidazo[4,5-c]quinoline of Formula XX is oxidized to provide an N-oxide of Formula XXI using a conventional oxidizing agent that is capable of forming N-oxides. The reaction can be carried out by treating a solution of a compound of Formula XX in a suitable solvent such as chloroform or dichloromethane with 3-chloroperoxybenzoic acid at ambient temperature. [0316]
  • In step (10) of Reaction Scheme II an N-oxide of Formula XXI is aminated to provide a 1H-imidazo[4,5-c]quinoline-4-amine of Formula XXII which is a subgenus of Formula II. The reaction is carried out in two parts. In part (i) a compound of Formula XXI is reacted with an acylating agent. Suitable acylating agents include alkyl- or arylsulfonyl chorides (e.g., benzenesulfonyl choride, methanesulfonyl choride, and p-toluenesulfonyl chloride). In part (ii) the product of part (i) is reacted with an excess of an aminating agent. Suitable aminating agents include ammonia (e.g. in the form of ammonium hydroxide) and ammonium salts (e.g., ammonium carbonate, ammonium bicarbonate, ammonium phosphate). The reaction can be carried out by dissolving a compound of Formula XXI in a suitable solvent such as dichloromethane or chloroform, adding ammonium hydroxide to the solution, and then adding p-toluenesulfonyl chloride. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods. [0317]
    Figure US20040147543A1-20040729-C00032
  • For some embodiments, compounds shown in Reaction Scheme II can be further elaborated using conventional synthetic methods. For example, an amine of Formula R[0318] 1b—NH2, where R1b is R4b and R4b is a subset of R4 that does not include those substitutents which one skilled in the art would recognize as being susceptible to oxidation in step (9), may be substituted by a hydroxy or second amino group, which can be further functionalized before step (7) of Reaction Scheme II. For example, a 3-nitroquinolin-4-amine of Formula XVIII, in which R1b is R4b having an amino substituent, can react with an acid chloride of Formula R4bC(O)Cl, a sulfonyl chloride of Formula R4bS(O)2Cl, or a sulfonic anhydride of Formula (R4bS(O)2)2O to provide a compound of Formula XVIII in which R1b is —X—Y—R4b, where Y is —N(R8)—Q—, R8 is as defined above, and Q is —C(O)— or —SO2—. Numerous acid chlorides, sulfonyl chlorides, and sulfonic anhydrides are commercially available; others can be readily prepared using known synthetic methods. The reaction can be conveniently carried out by adding an acid chloride of Formula R4bC(O)Cl, a sulfonyl chloride of Formula R4bS(O)2Cl, or a sulfonic anhydride of Formula (R4bS(O)2)2O to a solution of a 3-nitroquinolin-4-amine of Formula XVIII, in which R1b is R4b having an amino substituent, and a base such as triethylamine in a suitable solvent such as dichloromethane. The reaction can be carried out at ambient temperature.
  • A 3-nitroquinolin-4-amine of Formula XVIII, in which R[0319] 1b is R4b having an amino substituent, can also react with isocyanates of Formula R4bN═C═O to provide a compound of Formula XVIII in which R1b is —X—Y—R4b, where Y is —N(R8)—Q—, R8 is as defined above, and Q is —C(R6)—N(R8)—W—, R6 is ═O, and W is a bond. Numerous isocyanates of Formula R4bN═C═O are commercially available; others can be readily prepared using known synthetic methods. The reaction can be conveniently carried out by adding the isocyanate of Formula R4bN═C═O to a solution of the 3-nitroquinolin-4-amine of Formula XVIII, in which R1b is R4b having an amino substituent, in a suitable solvent such as dichloromethane. The reaction can be carried out at ambient temperature. Alternatively, a compound of Formula XVIII can be treated with an isocyanate of Formula R4b(CO)N═C═O, a thioisocyanate of Formula R4bN═C═S, a sulfonyl isocyanate of Formula R4bS(O)2N═C═O, or a carbamoyl chloride of Formula R4bN—(R8)—C(O)Cl or
    Figure US20040147543A1-20040729-C00033
  • to provide a compound of Formula XVIII, where Rib is —X—N(R[0320] 8)—Q—R4b or
    Figure US20040147543A1-20040729-C00034
  • Q is —C(R[0321] 6)—N(R8)—W—, and R6, R8, and W are as defined above. The product can then be treated according to steps (7) through (10) of Reaction Scheme II to provide 1H-imidazo[4,5-c]quinolin-4-amine of Formula XXII.
  • Compounds of the invention, where R[0322] 1c is —X—Y—R4b or —X—R5; Y is —N(R8)—Q—; R5 is
    Figure US20040147543A1-20040729-C00035
  • and X, Q, R, R[0323] 2, R3a, R4b, and n are as defined above can be prepared according to Reaction Scheme III. Steps (1) through (4) of Reaction Scheme III are carried out as described for steps (2) through (5) of Reaction Scheme II.
  • In step (5) of Reaction Scheme III, a 4-chloro-3-nitroquinoline of Formula XXVII is treated with a Boc-protected diamine of Formula (CH[0324] 3)3CO—C(O)—NH—X—NH2 to provide a protected 3-nitroquinolin-4-amine of Formula XXVIII. Several Boc-protected diamines of Formula (CH3)3CO—C(O)—NH—X—NH2 are commercially available; others can be prepared by known synthetic methods. The reaction is conveniently carried out by adding a solution of the Boc-protected diamine of Formula (CH3)3CO—C(O)—NH—X—NH2 to a cooled solution of a 4-chloro-3-nitroquinoline of Formula XXVII in a suitable solvent such as dichloromethane in the presence of a tertiary amine such as triethylamine. The reaction can be carried out at ambient temperature, and the product can be isolated using conventional methods.
  • In steps (6) and (7) of Reaction Scheme III, a 3-nitroquinolin-4-amine of Formula XXVIII is first reduced to provide a quinoline-3,4-diamine of Formula XXIX, which is converted to 1H-imidazo[4,5-c]quinoline of Formula XXX by reaction with a carboxylic acid equivalent. Steps (6) and (7) of Reaction Scheme III can be carried out as described for steps (7) and (8) of Reaction Scheme II. The sodium dithionite reduction in step (6) can also be conveniently carried out in a mixture of dichloromethane and water at ambient temperature in the presence of potassium carbonate and 1,1′-di-n-octyl-4,4′-bipyridinium dibromide. In part (ii) of step (7), the cyclization can also be carried out in ethanol while heated at reflux. [0325]
  • In step (8) of Reaction Scheme III, the Boc-protecting group of a 1H-imidazo[4,5-c]quinoline of Formula XXX is removed to provide a 1H-imidazo[4,5-c]quinoline of Formula XXXI. The reaction is conveniently carried out by adding hydrochloric acid or a solution of hydrochloric acid in ethanol to a solution of a 1H-imidazo[4,5-c]quinoline of Formula XXX in a suitable solvent such as ethanol. The reaction can be carried out at an elevated temperature, for example, the reflux temperature of the solvent. The product or pharmaceutically acceptable salt thereof can be isolated by conventional methods. [0326]
  • In step (9) of Reaction Scheme III, an amino-substituted 1H-imidazo[4,5-c]quinoline of Formula XXXI is converted to a 1H-imidazo[4,5-c]quinolin-1-yl compound of Formula XXXII, where R[0327] 1c is as defined above, using conventional methods. For example, a 1H-imidazo[4,5-c]quinoline of Formula XXXI can react with an acid chloride of Formula R4bC(O)Cl to provide a compound of Formula XXXII in which R1c is —X—Y—R4b, Y is —N(R8)—Q—, and Q is —C(O)—. In addition, a 1H-imidazo[4,5-c]quinoline of Formula XXXI can react with sulfonyl chloride of Formula R4bS(O)2Cl or a sulfonic anhydride of Formula (R4bS(O)2)2O to provide a compound of Formula XXXII in which R1c is —X—Y—R4b, Y is —N(R8)—Q—, and Q is —S(O)2—. Numerous acid chlorides of Formula R4bC(O)Cl, sulfonyl chlorides of Formula R4bS(O)2Cl, and sulfonic anhydrides of Formula (R4bS(O)2)2O are commercially available; others can be readily prepared using known synthetic methods. The reaction can be carried out as described above for a compound of Formula XVIII.
  • Ureas of Formula XXXII, where R[0328] 1c is —X—Y—R4b, Y is —N(R8)—Q—, Q is —C(R6)—N(R8)—W—, and W and R8 are as defined above can be prepared by reacting a 1H-imidazo[4,5-c]quinoline of Formula XXXI with isocyanates of Formula R4N═C═O or Formula R4(CO)N═C═O, thioisocyanates of Formula F4N═C═S, sulfonyl isocyanates of Formula R4S(O)2N═C═O, or carbamoyl chlorides of Formula R4N—(R8)—C(O)Cl. Numerous compounds of these types are commercially available; others can be readily prepared using known synthetic methods. The reaction can be carried out as described above for a compound of Formula XVIII.
  • Compounds of Formula XXXII where R[0329] 1c is —X—R5 and R5 is
    Figure US20040147543A1-20040729-C00036
  • can be prepared by treating an amino-substituted 1H-imidazo[4,5-c]quinoline of Formula XXXI with a chloroalkanesulfonyl chloride of Formula Cl—R[0330] 7S(O)2Cl. The reaction is conveniently carried out by adding the chloroalkanesulfonyl chloride to a solution of the amino-substituted 1H-imidazo[4,5-c]quinoline of Formula XXXI in a suitable solvent such as chloroform at ambient temperature. The isolable intermediate chloroalkanesulfonamide can then be treated with a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene at ambient temperature in a suitable solvent such as DMF to effect the cyclization. The product can be isolated using conventional methods.
  • In steps (10) and (11) of Reaction Scheme III, a 1H-imidazo[4,5-c]quinoline of Formula XXXII is oxidized to afford a 1H-imidazo[4,5-c]quinoline-5N-oxide of Formula XXXIII, which is aminated to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XXXIV. Steps (10) and (11) of Reaction Scheme III can be carried out as described for steps (9) and (10), respectively, of Reaction Scheme II. [0331]
  • In step (12) of Reaction Scheme III, a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XXXIV undergoes a coupling reaction with boronic acid of Formula X, an anhydride thereof, or a boronic acid ester of Formula R[0332] 3a—B(O-alkyl)2. The Suzuki coupling reaction can be carried out as described in Reaction Scheme I to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XXXV, which is a subgenus of Formula II. The product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
    Figure US20040147543A1-20040729-C00037
  • Compounds of the invention can also be prepared according to Reaction Scheme IV, where R, R[0333] 2, R3a, R4, R10, X, and Q are as defined above. In step (1) of Reaction Scheme IV, a 4-chloro-3-nitroquinoline of Formula XXVII is treated with a Boc-protected diamine of Formula XXXVI to provide a 3-nitroquinolin-4-amine of Formula XXXVII. Boc-protected diamines of Formula XXXVII are available from the method described by Carceller, E. et al, J. Med. Chem., 39, 487-493 (1996). The reaction can be carried out as described for step (5) of Reaction Scheme III.
  • In steps (2)-(5) of Reaction Scheme IV, a 3-nitroquinolin-4-amine of Formula XXXVII is first reduced to provide a quinoline-3,4-diamine of Formula XXXVIII, which is converted to 1H-imidazo[4,5-c]quinoline of Formula XXXIX by reaction with a carboxylic acid equivalent. The 1H-imidazo[4,5-c]quinoline of Formula XXXIX is then oxidized to afford a 1H-imidazo[4,5-c]quinoline-5N-oxide of Formula XL, which is aminated to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XLI. Steps (2), (3), (4), and (5) of Reaction Scheme IV can be carried out as described for steps (7), (8), (9), and (10), respectively, of Reaction Scheme II. [0334]
  • In steps (6) of Reaction Scheme IV, the Boc protecting group of a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XLI is removed to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XLII, which is converted to a 1H-imidazo[4,5-c]quinolinyl compound of Formula XLIII in step (7). Steps (6) and (7) of Reaction Scheme IV can be carried out as described for steps (8) and (9) of Reaction Scheme III. [0335]
  • In step (8), the compound of Formula XLIII is then coupled with a boronic acid of Formula X, an anhydride thereof, or boronic acid ester of Formula R[0336] 3a—B(O-alkyl)2 to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XLIV, which is a subgenus of Formula II. The Suzuki coupling reaction can be carried out as described in Reaction Scheme I. In some embodiments, the coupling reaction shown in step (8) is carried out prior to the deprotection and functionalization reactions shown in steps (6) and (7) to provide a compound of Formula XLIV. The product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
    Figure US20040147543A1-20040729-C00038
  • The Heck reaction can be used to prepare compounds of the invention as shown in step (1) of Reaction Scheme V, wherein R[0337] 1,R2, R, Hal, and n are as defined above and Ara is —Ar, —Ar′—Y—R4, or —Ar′—X—Y—R4. In step (1) of Reaction Scheme V, a halogen-substituted imidazoquinolin-4-amine of Formula IX is coupled with a vinyl-substituted compound of Formula L to provide an imidazoquinolin-4-amine of Formula LI, which is a subgenus of Formula II. Alternatively, a compound of Formula L can be coupled with a trifluoromethanesulfonate-substituted imidazoquinolin-4-amine, in which Hal in Formula IX is replaced by —OSO2CF3. Several compounds of Formula L are commercially available; others can be prepared by known methods. The reaction is conveniently carried out by combining the imidazoquinolin-4-amine of Formula IX and the vinyl-substituted compound of Formula L in the presence of palladium (II) acetate, triphenylphosphine or tri-ortho-tolylphosphine, and a base such as triethylamine in a suitable solvent such as acetonitrile or toluene. The reaction can be carried out at an elevated temperature such as 100-120° C. under an inert atmosphere. The compound or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • In step (2) of Reaction Scheme V, the vinyl group of an imidazoquinolin-4-amine of Formula LI is reduced to provide an imidazoquinolin-4-amine of Formula LII, which is also a subgenus of Formula II. The reduction can be carried out by hydrogenation using a conventional heterogeneous hydrogenation catalyst such as palladium on carbon. The reaction can conveniently be carried out on a Parr apparatus in a suitable solvent such as ethanol, methanol, or mixtures thereof. The compound or pharmaceutically acceptable salt thereof can be isolated using conventional methods. [0338]
    Figure US20040147543A1-20040729-C00039
  • Palladium-catalyzed coupling reactions can also be used to prepare compounds of the invention according to Reaction Scheme VI, wherein R[0339] 1, R2, R9, R, Hal, Ara, and n are as defined above. In step (1) of Reaction Scheme VI, a halogen-substituted imidazoquinolin-4-amine of Formula IX undergoes a Suzuki-type coupling with a potassium alkenyltrifluoroborate of Formula LIII to provide an imidazoquinolin-4-amine of Formula XLVII. The reaction is conveniently carried out by combining the imidazoquinolin-4-amine of Formula IX and a compound of Formula LIII, such as potassium vinyltrifluoroborate, in the presence of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct and a base such as triethylamine in a suitable solvent such as n-propanol. The reaction can be carried out at an elevated temperature such as the reflux temperature of the solvent under an inert atmosphere. The compound or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • In step (2) of Reaction Scheme VI, the Heck reaction is used to couple a vinylated imidazoquinolin-4-amine of Formula XLVII with an aryl or hetereoaryl halide of Formula Ar[0340] a-Hal or a trifluoromethanesulfonate of Formula Ara—OSO2CF3. Numerous compounds of Formula Ara-Hal are commercially available; others can be prepared using known synthetic methods. The reaction is conveniently carried out under the conditions described in step (1) of Reaction Scheme V to provide an imidazoquinolin-4-amine of Formula LI. The product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • In step (3) of Reaction Scheme VI, the vinyl group of an imidazoquinolin-4-amine of Formula LI is reduced to provide an imidazoquinolin-4-amine of Formula LII. The reaction is conveniently carried out by hydrogenation under the conditions described in step (2) of Reaction Scheme V. [0341]
    Figure US20040147543A1-20040729-C00040
  • Dimers of the invention can be prepared according to Reaction Scheme VII, wherein R[0342] 1, R2, Z, Hal, and Ar′ are as defined above. In Reaction Scheme VII, a Suzuki coupling is carried out with an imidazoquinolin-4-amine of Formula LIV and a difunctional boronic acid of Formula LV, or an ester or anhydride thereof. Some boronic acids of Formula LV are commercially available; others can be prepared by known synthetic methods. The coupling can be carried out as described in Reaction Scheme I to provide a dimer of Formula XLVI. The compound or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
    Figure US20040147543A1-20040729-C00041
  • Compounds of the invention can also be prepared according to Reaction Scheme VIII, wherein R, R[0343] 3a, n, and Hal are as defined above, and R1d and R2d are subsets of R1 and R2 that do not include substituents that one skilled in the art would recognize as being susceptible to nucleophilic attack in step (5). These groups include, for example, esters and ureas. In step (1) of Reaction Scheme VIII, a nitro-substituted quinoline-2,4-diol of Formula LVI is chlorinated to provide a 2,4-dichloroquinoline of Formula LVII. Nitro-substituted quinoline-2,4-diols of Formula LVI can be prepared from substituted anilines according to the methods described in Buckle et al, J. Med. Chem., 18, 726-732 (1975). The chlorination is conveniently carried out by heating the compound of Formula LVI and phenylphosphonic dichloride at an elevated temperature such as 140° C. The reaction can be carried out without solvent, and the product can be isolated using conventional methods.
  • In step (2) of Reaction Scheme VIII, a 2,4-dichloroquinoline of Formula LVII is reacted with an amine of Formula R[0344] 1—NH2 to provide a 2-chloro-3-nitroquinolin-4-amine of Formula LVIII. The reaction can be carried out as described in step (6) of Reaction Scheme II.
  • In step (3) of Reaction Scheme VIII, the nitro group of a 2-chloro-3-nitroquinolin-4-amine of Formula LVIII is reduced to provide a 2-chloroquinoline-3,4-diamine of Formula LIX. The reduction is conveniently carried out with sodium dithionite according to the method described in step (7) of Reaction Scheme II. [0345]
  • In step (4) of Reaction Scheme VIII, a 2-chloroquinoline-3,4-diamine of Formula LIX is treated with a carboxylic acid or an equivalent thereof to provide a 4-chloro-1H-imidazo[4,5-c]quinoline of Formula LX. The reaction can be carried out as described in step (8) of Reaction Scheme II. [0346]
  • In step (5) of Reaction Scheme VIII, a 4-chloro-1H-imidazo[4,5-c]quinoline of Formula LX is aminated to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula LXI. The reaction is conveniently carried out by combining the compound of Formula LX with a solution of ammonia in methanol in a bomb reactor and heating at an elevated temperature, such as 120° C. The product or pharmaceutically acceptable salt thereof can be isolated using conventional methods. [0347]
  • In step (6) of Reaction Scheme VIII, a 1H-imidazo[4,5-c]quinolin-4-amine of Formula LXI undergoes a coupling reaction with a boronic acid of Formula X, an anhydride thereof, or a boronic acid ester of Formula R[0348] 3a—B(O-alkyl)2. The Suzuki coupling reaction can be carried out as described in Reaction Scheme I to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula LXII, which is a subgenus of Formula II. The product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
    Figure US20040147543A1-20040729-C00042
  • For some embodiments, compounds of the invention are prepared according to Reaction Scheme IX, where R, R[0349] 2, R3a, R4, X, Q, and n are as defined above. In step (1) of Reaction Scheme IX, a 4-chloro-3-nitroquinoline of Formula XXVII is treated with a Boc-protected piperazine of Formula LXIII to provide a 3-nitroquinolin-4-amine of Formula LXIV. The reaction can be carried out as described for step (5) of Reaction Scheme III.
  • In steps (2) and (3) of Reaction Scheme IX, a 3-nitroquinolin-4-amine of Formula LXIV is first reduced to provide a quinoline-3,4-diamine of Formula LXV, which is converted to 1H-imidazo[4,5-c]quinoline of Formula LXVI by reaction with a carboxylic acid equivalent. Step (2) of Reaction Scheme IX can be carried out as described for step (7) of Reaction Scheme II or step (8) of Reaction Scheme III. Step (3) of Reaction Scheme IX can be carried out as described for step (8) of Reaction Scheme II. [0350]
  • The 1H-imidazo[4,5-c]quinoline of Formula LXVI is then oxidized in step (4) of Reaction Scheme IX to afford a dioxido-1H-imidazo[4,5-c]quinoline of Formula LXVII. The oxidation reaction is conveniently carried out in a similar manner to step (9) of Reaction Scheme II but with additional equivalents of 3-chloroperoxybenzoic acid. The product can be isolated using conventional methods. [0351]
  • In step (5) of Reaction Scheme IX, a dioxido-1H-imidazo[4,5-c]quinoline of Formula LXVII is aminated to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula LXVIII. Step (5) of Reaction Scheme IX can be carried out as described for step (10) of Reaction Scheme II. [0352]
  • In step (6) of Reaction Scheme IX, the piperazine N-oxide of the 1H-imidazo[4,5-c]quinolin-4-amine of Formula LXVIII is reduced to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula LXIX. The reaction is conveniently carried out by adding phosphorous trichloride to an N-oxide of Formula LXVIII in a suitable solvent such as chloroform. The reaction can be carried out at a subambient temperature, such as 4° C. The product can be isolated using conventional methods. [0353]
  • In step (7) of Reaction Scheme IX, the Boc protecting group of a 1H-imidazo[4,5-c]quinolin-4-amine of Formula LXIX is removed to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula LXX. The deprotection can be carried out as described in step (8) of Reaction Scheme III. [0354]
  • In step (8) of Reaction Scheme IX, a 1H-imidazo[4,5-c]quinolin-4-amine of Formula LXX is coupled with a boronic acid of Formula X, an anhydride thereof, or boronic acid ester of Formula R[0355] 3a—B(O-alkyl)2 to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula LXXI, which is a subgenus of Formula II. The Suzuki coupling reaction can be carried out as described in Reaction Scheme I. The product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • In step (9) of Reaction Scheme IX, a 1H-imidazo[4,5-c]quinolin-4-amine of Formula LXXI is converted to a 1H-imidazo[4,5-c]quinolinyl compound of Formula LXXII. Step (9) can be carried out as described for step (9) of Reaction Scheme III, and the product or pharmaceutically acceptable salt thereof can be isolated using conventional methods. [0356]
    Figure US20040147543A1-20040729-C00043
  • For certain embodiments, compounds of the invention can be prepared according to Reaction Scheme X, where R, R[0357] 2, R4, Hal, and n are as defined above and X1-1 is selected from the group consisting of C1-10alkylene, C4-10alkenylene, and C4-10alkynylene, wherein the terminal carbon atoms of alkenylene and alkynylene are tetrahedral. In step (1) a 3-nitroquinolin-4-amine of Formula LXXIII is reduced to provide a quinoline-3,4-diamine of Formula LXXIV. The reaction can be carried out as in step (7) of Reaction Scheme II. The product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods. Many 3-nitroquinolin-4-amines of Formula LXXIII are known or can be prepared using known synthetic methods, see for exarnple, U.S. Pat. Nos. 4,689,338; 5,175,296; and 5,389,640; and the references cited therein.
  • In step (2) of Reaction Scheme X, a quinoline-3,4-diamine of Formula LXXIV is reacted with a carboxylic acid or an equivalent thereof to provide a 1H-imidazo[4,5-c]quinoline of Formula LXXV. The reaction can be conveniently carried out as described in step (8) of Reaction Scheme II. The product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods. [0358]
  • In step (3) of Reaction Scheme X, a 1H-imidazo[4,5-c]quinoline of Formula LXXV is reacted with sodium hydride to form an alkoxide, which is reacted with a vinyl sulfone to provide a 1H-imidazo[4,5-c]quinoline of Formula LXXVI. The reaction can be carried out by adding catalytic sodium hydride dispersed in mineral oil to a solution of a 1H-imidazo[4,5-c]quinoline of Formula LXXV and a vinyl sulfone of the formula CH[0359] 2═CH—S(O)2—R4 in a suitable solvent such DMF or tetrahydrofuran. The reaction can be run at ambient temperature. The product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • In step (4) of Reaction Scheme X, a 1H-imidazo[4,5-c]quinoline of Formula LXXVI is oxidized to provide an N-oxide of Formula LXXVII. The reaction can be conveniently carried out as in step (9) of Reaction Scheme II. [0360]
  • In step (5) an N-oxide of Formula LXXVII is aminated to provide a 1H-imidazo[4,5-c]quinoline-4-amine of Formula LXXVIII. The reaction is carried as in step (10) of Reaction Scheme II. The product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods. [0361]
  • In step (6) of Reaction Scheme X, a halogen-substituted 1H-imidazo[4,5-c]quinoline-4-amine of Formula LXXVIII undergoes a coupling reaction with a boronic acid of Formula X, an anhydride thereof, or a boronic acid ester of Formula R[0362] 3a—B(O-alkyl)2. The Suzuki coupling reaction can be carried out as described in Reaction Scheme I to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula LXXIX, which is a subgenus of Formula II. The product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
    Figure US20040147543A1-20040729-C00044
  • For other embodiments, compounds of the invention can be prepared according to Reaction Scheme XI, where R, R[0363] 2, R4, R8, X, Hal, and n are as defined above. In step (1) of Reaction Scheme XI, the hydroxy group of a 3-nitroquinolin-4-amine of Formula LXXX is chlorinated using conventional methods to provide a 3-nitroquinolin-4-amine of Formula LXXXI. Many 3-nitroquinolin-4-amines of Formula LXXIII are known or can be prepared using known synthetic methods, see for example, U.S. Pat. Nos. 4,689,338; 5,175,296; and 5,389,640; and the references cited therein. The chlorination is conveniently carried out by adding thionyl chloride to a solution of the 3-nitroquinolin-4-amine of Formula LXXX in a suitable solvent such as dichloromethane. The reaction can be carried out at ambient temperature, and the product can be isolated using conventional methods.
  • In step (2) of Reaction Scheme XI, a 3-nitroquinolin-4-amine of Formula LXXXI is reduced to provide a quinoline-3,4-diamine of Formula LXXXII. The reduction can be carried out with sodium dithionite as described in step (7) of Reaction Scheme II. The product can be isolated by conventional methods. [0364]
  • In step (3) of Reaction Scheme XI, a quinoline-3,4-diamine of Formula LXXXII is reacted with a carboxylic acid or an equivalent thereof to provide a 1H-imidazo[4,5-c]quinoline of Formula LXXXIII. The reaction can be conveniently carried out as described in step (8) of Reaction Scheme II; the product can be isolated by conventional methods. [0365]
  • In step (4) of Reaction Scheme XI, the chloro group of a 1H-imidazo[4,5-c]quinoline of Formula LXXXIII is displaced with potassium thioacetate to provide a 1H-imidazo[4,5-c]quinoline of Formula LXXXIV. The reaction is conveniently carried out by adding potassium thioacetate to a solution of a 1H-imidazo[4,5-c]quinoline of Formula LXXXIII in a suitable solvent such as DMF. The reaction can be carried out at ambient temperature, and the product can be isolated using conventional methods. [0366]
  • In step (5) of Reaction Scheme XI, the thioacetate group of a 1H-imidazo[4,5-c]quinoline of Formula LXXXIV is hydrolyzed under basic conditions to provide a thiol-substituted 1H-imidazo[4,5-c]quinoline of Formula LXXXV. The reaction is conveniently carried out by adding a solution of sodium methoxide in methanol to a solution of a 1H-imidazo[4,5-c]quinoline of Formula LXXXIV in methanol. The reaction can be carried out at ambient temperature, and the product can be isolated using conventional methods. [0367]
  • In step (6) of Reaction Scheme XI, the thiol group of a 1H-imidazo[4,5-c]quinoline of Formula LXXXV is oxidized to a sulfonyl chloride of Formula LXXXVI. The reaction is conveniently carried out by adding a solution of sodium chlorate in a suitable solvent such as water to a solution of a thiol-substituted 1H-imidazo[4,5-c]quinoline of Formula LXXXV in hydrochloric acid. The reaction can be carried out at a subambient temperature such as 0° C., and the product can be isolated using conventional methods. [0368]
  • Alternatively, steps (4), (5), and (6) can be replaced with steps (4a) and (5a) of Reaction Scheme XI. In step (4a), the chloro group of a 1H-imidazo[4,5-c]quinoline of Formula LXXXIII is displaced with thiourea to provide a 1H-imidazo[4,5-c]quinoline of Formula LXXXVII. The reaction is conveniently carried out by adding thiourea and a catalytic amount of potassium iodide to a solution of a 1H-imidazo[4,5-c]quinoline of Formula LXXXIII in a suitable solvent such as DMF. The reaction can be carried out at an elevated temperature, such as 110° C., and the product can be isolated using conventional methods. [0369]
  • In step (5a) of Reaction Scheme XI, the thiourea group of a 1H-imidazo[4,5-c]quinoline of Formula LXXXVII is converted to a sulfonyl chloride of Formula LXXXVI under the conditions described in step (6). [0370]
  • In step (7) of Reaction Scheme XI, the sulfonyl chloride of Formula LXXXVI is treated with an amine or an amine salt to provide a sulfonamide of Formula LXXXVIII. The reaction is conveniently carried out by adding an amine of Formula NH(R[0371] 4)(R8) to a sulfonyl chloride of Formula LXXXVI in a suitable solvent such as dichloromethane. The reaction can be carried out at ambient temperature, and the product can be isolated using conventional methods. Alternatively, step (7) can be carried out by adding an amine hydrochloride of Formula (R4)(R8)NH.HCl followed by aqueous potassium carbonate to a solution of a sulfonyl chloride of Formula LXXXVI in a suitable solvent such as dichloromethane. The reaction can be carried out at ambient temperature, and the product can be isolated using conventional methods.
  • In steps (8) and (9) of Reaction Scheme XI, a sulfonamide-substituted 1H-imidazo[4,5-c]quinoline of Formula LXXXVIII is oxidized in step (8) to afford a 1H-imidazo[4,5-c]quinoline-5N-oxide of Formula LXXXIX, which is aminated in step (9) to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XC. Steps (8) and (9) of Reaction Scheme XI can be carried out as described in steps (9) and (10) of Reaction Scheme II. [0372]
  • In step (10) of Reaction Scheme XI, a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XC is coupled with a boronic acid of Formula X, an anhydride thereof, or boronic acid ester of Formula R[0373] 3a—B(O-alkyl)2 to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XCI, which is a subgenus of Formula II. Step (10) can be carried out as described in Reaction Scheme I. The product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
    Figure US20040147543A1-20040729-C00045
  • For other embodiments, compounds of the invention can be prepared according to Reaction Scheme XII, wherein R, R[0374] 1, R2, Hal, and n are as defined above, and HA is a heteroaryl group attached at a nitrogen atom. In Reaction Scheme XII, a halogen-substituted imidazoquinolin-4-amine of Formula IX undergoes a copper-catalyzed amination with a nitrogen-containing heteroaryl compound to provide an imidazoquinolin-4-amine of Formula XClI, which is a subgenus of Formula II. Several nitrogen-containing heteroaryl compounds, such as imidazole and pyrazole, are commercially available; others can be prepared by known methods. The reaction is conveniently carried out by combining the imidazoquinolin-4-amine of Formula IX and the nitrogen-containing heteroaryl compound in the presence of copper (I) iodide, potassium phosphate, and trans-1,2-diaminocyclohexane in a suitable solvent such as 1,4-dioxane. The reaction can be carried out at an elevated temperature such as 110° C. The compound or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
    Figure US20040147543A1-20040729-C00046
  • Pharmaceutical Compositions and Biological Activity [0375]
  • Pharmaceutical compositions of the invention contain a therapeutically effective amount of a compound of the invention as described above in combination with a pharmaceutically acceptable carrier. [0376]
  • The term “therapeutically effective amount” or “effective amount” means an amount of the compound sufficient to induce a therapeutic or prophylactic effect, such as cytokine induction, cytokine inhibition, immunomodulation, antitumor activity, and/or antiviral activity. Although the exact amount of active compound used in a pharmaceutical composition of the invention will vary according to factors known to those of skill in the art, such as the physical and chemical nature of the compound, the nature of the carrier, and the intended dosing regimen, it is anticipated that the compositions of the invention will contain sufficient active ingredient to provide a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 μg/kg to about 5 mg/kg, of the compound to the subject. A variety of dosage forms may be used, such as tablets, lozenges, capsules, parenteral formulations, syrups, creams, ointments, aerosol formulations, transderrnal patches, transmucosal patches and the like. [0377]
  • The compounds of the invention can be administered as the single therapeutic agent in the treatment regimen, or the compounds of the invention may be administered in combination with one another or with other active agents, including additional immune response modifiers, antivirals, antibiotics, antibodies, proteins, peptides, oligonucleotides, etc. [0378]
  • Compounds of the invention have been shown to modulate (e.g., induce or inhibit) the production of certain cytokines in experiments performed according to the tests set forth below. These results indicate that compounds of the invention are useful as immune response modifiers that can modulate the immune response in a number of different ways, rendering them useful in the treatment of a variety of disorders. [0379]
  • Cytokines whose production may be induced by the administration of certain compounds according to the invention generally include interferon-a (IFN-α) and/or tumor necrosis factor-α (TNF-α) as well as certain interleukins (IL). Cytokines whose biosynthesis may be induced by certain compounds of the invention include IFN-α, TNF-α, IL-1, IL-6, IL-10 and IL-12, and a variety of other cytokines. Among other effects, these and other cytokines can inhibit virus production and tumor cell growth, making the compounds useful in the treatment of viral diseases and neoplastic diseases. Accordingly, the invention provides a method of inducing cytokine biosynthesis in an animal comprising administering an effective amount of a compound or composition of the invention to the animal. The animal to which the compound or composition is administered for induction of cytokine biosynthesis may have a disease as described infra, for example a viral disease or a neoplastic disease, and administration of the compound may provide therapeutic treatment. Alternatively, the compound may be administered to the animal prior to the animal aquiring the disease so that administration of the compound may provide a prophylactic treatment. [0380]
  • In addition to the ability to induce the production of cytokines, certain compounds of the invention affect other aspects of the innate immune response. For example, natural killer cell activity may be stimulated, an effect that may be due to cytokine induction. Certain compounds may also activate macrophages, which in turn stimulate secretion of nitric oxide and the production of additional cytokines. Further, certain compounds may cause proliferation and differentiation of B-lymphocytes. [0381]
  • Certain compounds of the invention also have an effect on the acquired immune response. For example, the production of the T helper type 1 (T[0382] H1) cytokine IFN-γ is induced indirectly and the production of the T helper type 2 (TH2) cytokines IL-4, IL-5 and IL-13 are inhibited upon administration of compounds of the invention.
  • Other cytokines whose production is inhibited by the administration of certain compounds according to the invention include tumor necrosis factor-α (TNF-α). Among other effects, inhibition of TNF-α production can provide prophylaxis or therapeutic treatment of diseases in animals in which TNF is mediated, making the compounds useful in the treatment of, for example, autoimmune diseases. Accordingly, the invention provides a method of inhibiting TNF-α biosynthesis in an animal comprising administering an effective amount of a compound or composition of the invention to the animal. The animal to which the compound or composition is administered for inhibition of TNF-α biosynthesis may have a disease as described infra, for example an autoimmune disease, and administration of the compound may provide therapeutic treatment. Alternatively, the compound may be administered to the animal prior to the animal aquiring the disease so that administration of the compound may provide a prophylactic treatment. [0383]
  • Whether for prophylaxis or therapeutic treatment of a disease, and whether for effecting innate or acquired immunity, the compound or composition may be administered alone or in combination with one or more active components as in, for example, a vaccine adjuvant. When administered with other components, the compound and other component or components may be administered separately; together but independently such as in a solution; or together and associated with one another such as (a) covalently linked or (b) non-covalently associated, e.g., in a colloidal suspension. [0384]
  • Conditions for which IRMs identified herein may be used as treatments include, but are not limited to: [0385]
  • (a) viral diseases such as, for example, diseases resulting from infection by an adenovirus, a herpesvirus (e.g., HSV-I, HSV-II, CMV, or VZV), a poxvirus (e.g., an orthopoxvirus such as variola or vaccinia, or molluscum contagiosum), a picomavirus (e.g., rhinovirus or enterovirus), an orthomyxovirus (e.g., influenzavirus), a paramyxovirus (e.g., parainfluenzavirus, mumps virus, measles virus, and respiratory syncytial virus (RSV)), a coronavirus (e.g., SARS), a papovavirus (e.g., papillomaviruses, such as those that cause genital warts, common warts, or plantar warts), a hepadnavirus (e.g., hepatitis B virus), a flavivirus (e.g., hepatitis C virus or Dengue virus), or a retrovirus (e.g., a lentivirus such as HIV); [0386]
  • (b) bacterial diseases such as, for example, diseases resulting from infection by bacteria of, for example, the genus Escherichia, Enterobacter, Salmonella, Staphylococcus, Shigella, Listeria, Aerobacter, Helicobacter, Klebsiella, Proteus, Pseudomonas, Streptococcus, Chlamydia, Mycoplasma, Pneumococcus, Neisseria, Clostridium, Bacillus, Corynebacterium, Mycobacterium, Campylobacter, Vibrio, Serratia, Providencia, Chromobacterium, Brucella, Yersinia, Haemophilus, or Bordetella; [0387]
  • (c) other infectious diseases, such chlamydia, fungal diseases including but not limited to candidiasis, aspergillosis, histoplasmosis, cryptococcal meningitis, or parasitic diseases including but not limited to malaria, pneumocystis camii pneumonia, leishmaniasis, cryptosporidiosis, toxoplasmosis, and trypanosome infection; and [0388]
  • (d) neoplastic diseases, such as intraepithelial neoplasias, cervical dysplasia, actinic keratosis, basal cell carcinoma, squamous cell carcinoma, renal cell carcinoma, Kaposi's sarcoma, melanoma, renal cell carcinoma, leukemias including but not limited to myelogeous leukemia, chronic lymphocytic leukemia, multiple myeloma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, B-cell lymphoma, and hairy cell leukemia, and other cancers; and [0389]
  • (e) T[0390] H2-mediated, atopic, and autoimmune diseases, such as atopic dermatitis or eczema, eosinophilia, asthma, allergy, allergic rhinitis, systemic lupus erythematosus, essential thrombocythaemia, multiple sclerosis, Ommen's syndrome, discoid lupus, alopecia areata, inhibition of keloid formation and other types of scarring, and enhancing would healing, including chronic wounds.
  • IRMs identified herein also may be useful as a vaccine adjuvant for use in conjunction with any material that raises either humoral and/or cell mediated immune response, such as, for example, live viral, bacterial, or parasitic immunogens; inactivated viral, tumor-derived, protozoal, organism-derived, fungal, or bacterial immunogens, toxoids, toxins; self-antigens; polysaccharides; proteins; glycoproteins; peptides; cellular vaccines; DNA vaccines; recombinant proteins; glycoproteins; peptides; and the like, for use in connection with, for example, BCG, cholera, plague, typhoid, hepatitis A, hepatitis B, hepatitis C, influenza A, influenza B, parainfluenza, polio, rabies, measles, mumps, rubella, yellow fever, tetanus, diphtheria, hemophilus influenza b, tuberculosis, meningococcal and pneumococcal vaccines, adenovirus, HIV, chicken pox, cytomegalovirus, dengue, feline leukemia, fowl plague, HSV-1 and HSV-2, hog cholera, Japanese encephalitis, respiratory syncytial virus, rotavirus, papilloma virus, yellow fever, and Alzheimer's Disease. [0391]
  • IRMs may also be particularly helpful in individuals having compromised immune function. For example, IRM compounds may be used for treating the opportunistic infections and tumors that occur after suppression of cell mediated immunity in, for example, transplant patients, cancer patients and HIV patients. [0392]
  • Thus, one or more of the above diseases or types of diseases, for example, a viral disease, a neoplastic disease, may be treated in an animal in need there of (having the disease) by administering a therapeutically effective amount of a compound or salt of Formula I, II, III, IV, V, VI, VII, VIII, XLVI, or a combination thereof to the animal. [0393]
  • An amount of a compound effective to induce or inhibit cytokine biosynthesis is an amount sufficient to cause one or more cell types, such as monocytes, macrophages, dendritic cells and B-cells to produce an amount of one or more cytokines such as, for example, IFN-α, TNF-α, IL-1, IL-6, IL-10 and IL-12 that is increased (induced) or decreased (inhibited) over a background level of such cytokines. The precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 μg/kg to about 5 mg/kg. The invention also provides a method of treating a viral infection in an animal and a method of treating a neoplastic disease in an animal comprising administering an effective amount of a compound or composition of the invention to the animal. An amount effective to treat or inhibit a viral infection is an amount that will cause a reduction in one or more of the manifestations of viral infection, such as viral lesions, viral load, rate of virus production, and mortality as compared to untreated control animals. The precise amount that is effective for such treatment will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 μg/kg to about 5 mg/kg. An amount of a compound effective to treat a neoplastic condition is an amount that will cause a reduction in tumor size or in the number of tumor foci. Again, the precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 μg/kg to about 5 mg/kg. [0394]
  • In addition to the formulations and uses described specifically herein, other formulations, uses, and administration devices suitable for compounds of the present invention are described in, for example, International Publication Nos. WO 03/077944, WO 03/080114, WO 03/045494, WO 02/024225, WO 02/036592, U.S. Pat. No. 6,245,776, and U.S. Publication Nos. 2002/0193729 and 2003/0139364. [0395]
  • Objects and advantages of this invention are further illustrated by the following examples, but the particular materials and amounts thereof recited in these examples, as well as other conditions and details, should not be construed to unduly limit this invention. [0396]
  • EXAMPLES
  • In the examples below some of the compounds were purified by preparative high performance liquid chromatography (prep HPLC) using a Waters Fraction Lynx automated purification system. The prep HPLC fractions were analyzed using a Micromass LC-TOFMS and the appropriate fractions were combined and centrifuge evaporated to provide the trifluoroacetate salt of the desired compound. In order to maximize purity, the compounds were sent through the purification process twice. Column: Phenomenex Luna C18(2), 21.2×50 millimeters (mm), 10 micron particle size, 100 Angstrom (Å) pore; flow rate: 25 milliliters per minutes (mL/min); non-linear gradient elution from 5-95% B in 9 min (first purification run) and from 5-65% B in 16 min (second purification run), then hold at 95% B for 2 min, where A is 0.05% trifluoroacetic acid/water and B is 0.05% trifluoroactic acid/acetonitrile; fraction collection by mass-selective triggering. [0397]
  • A variety of chromatographic conditions were used for the prep HPLC purification of other compounds shown in the examples below using either the Phenomenex Luna C18(2) column (21.2×50 millimeters (mm), 10 micron particle size) or a Waters Xterra C18 column (19×50 mm, 5 micron particle size). Elution was carried out in a non-linear gradient from 95:5 to 5:95 A:B, where A is 0.05% trifluoroacetic acid/water and B is 0.05% trifluoroactic acid/acetonitrile; fraction collection was performed by mass-selective triggering. [0398]
  • Some of the compounds prepared by Suzuki coupling were passed through a Waters Oasis Sample Extractions Cartridge MCX (6 cc) prior to prep HPLC purification. The following procedure was used. The product from the coupling reaction was dissolved in 1N hydrochloric acid (3 mL) to adjust to pH 5-7 and passed through the cartridge optionally using light nitrogen pressure. The cartridge was washed with methanol (5 mL) optionally using light nitrogen pressure and transferred to a clean test tube. A solution of 1% ammonia in methanol (2×5 mL) was then passed through the cartridge optionally using light nitrogen pressure, and the basic solution was collected and concentrated. [0399]
  • Example 1 2-Butyl-1-isobutyl-7-(thiophen-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine
  • [0400]
    Figure US20040147543A1-20040729-C00047
  • Part A [0401]
  • A mixture of triethyl orthoformate (154 grams (g), 1.04 moles (mol) and Meldrum's acid (142 g, 0.983 mol) was heated to 55° C. for 4 hours (h). After cooling to 50° C., a solution of 3-bromoaniline (162.6 g, 0.945 mol) in ethanol (300 mL) was added such that the temperature of the reaction was maintained between 50-55° C. After half of the 3-bromoaniline had been added, stirring became difficult due to the formation of solids, so more ethanol (1 liter (L)) was added to facilitate stirring. Upon complete addition, the reaction was cooled to room temperature (RT), and the solids were collected by filtration. The filter cake was washed with ice cold ethanol until the washings were nearly colorless, and the product was dried at 65° C. under vacuum to afford 287 g of 5-[(3-bromophenylamino)methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione as an off-white solid. [0402]
  • [0403] 1H NMR (300 MHz, CDCl3) δ 11.19 (brd, J=12.8 Hz, 1H), 8.60 (d, J=14.0 Hz, 1H), 7.44-7.38 (m, 2H), 7.30 (t, J=8.0 Hz, 1H), 7.18 (ddd, J=8.0, 2.2, 0.9 Hz, 1H), 1.75 (s, 6H).
  • Part B [0404]
  • 7-Bromoquinolin-4-ol was prepared in accordance with the literature procedure (D. Dibyendu et al., [0405] J. Med. Chem., 41, 4918-4926 (1998)) or by thermolysis of 5-[(3-bromophenylamino)methylene] -2,2-dimethyl-[1,3]dioxane-4,6-dione in DOWTHERM A heat transfer fluid and had the following spectral properties: 1H NMR (300 MHz, d6-DMSO) δ 11.70 (brs, 1H), 8.00 (d, J=8.7 Hz, 1H), 7.92 (d, J=7.5 Hz, 1H), 7.74 (d, J=1.9 Hz, 1H), 7.44 (dd, J=8.7, 1.9 Hz, 1H), 6.05 (d, J=7.5 Hz, 1H).
  • Part C [0406]
  • A stirred suspension of 7-bromoquinolin-4-ol (162 g, 0.723 mol) in propionic acid (1500 mL) was brought to 110° C. 70% Nitric acid (85 g) was added dropwise over 1 h such that the temperature was maintained between 110-115° C. After half of the nitric acid had been added, stirring became difficult due to the formation of solids and an additional 200 mL of propionic acid was added. Upon complete addition, the reaction was stirred for 1 h at 110° C., cooled to room temperature, and the solid was collected by filtration. The filter cake was washed with ice cold ethanol until the washings were nearly colorless (800 mL), and the product was dried at 60° C. under vacuum to afford 152 g of 7-bromo-3-nitro-quinolin-4-ol as a pale yellow solid. [0407]
  • [0408] 1H NMR (300 MHz, d6-DMSO) δ 13.0 (brs, 1H), 9.22 (s, 1H), 8.15 (d, J=8.4 Hz, 1H), 7.90 (d, J=1.6 Hz, 1H), 7.66 (dd, J=8.7, 1.9 Hz, 1H).
  • Part D [0409]
  • 7-Bromo-3-nitroquinolin-4-ol (42 g, 156 millimoles (mmol)) was suspended in POCl[0410] 3 (130 mL) and brought to 102° C. under an atmosphere of N2. After 45 min, all of the solids had dissolved, so the reaction was cooled to room temperature (RT). The resulting solids were collected by filtration, washed with H2O, and then partitioned with CH2Cl2 (3 L) and 2M Na2CO3 (500 mL). The organic layer was separated, washed with H2O (1×), dried over Na2SO4, filtered, and concentrated to afford 33.7 g of 7-bromo-4-chloro-3-nitroquinoline as a beige solid.
  • [0411] 1H NMR (300 MHz, CDCl3) δ 9.26 (s, 1H), 8.41 (d, J=1.8 Hz, 1H), 8.30 (d, J=9.0 Hz, 1H), 7.90 (dd, J=8.9, 2.1 Hz, 1H).
  • Part E [0412]
  • 7-Bromo-4-chloro-3-nitroquinoline (33.5 g, 117 mmol) and Et[0413] 3N (13.0 g, 128 mmol) were dissolved in CH2Cl2 (500 mL) and cooled on an ice bath. Isobutylamine (9.36 g, 128 mmol) was added in one portion and then the reaction was allowed to warm to room temperature. After 2 h, the reaction mixture was washed with water (500 mL), and the aqueous layer was extracted with CH2Cl2 (2×100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to afford 38.0 g of a yellow solid. Recrystallization from refluxing isopropanol (1.1 L) afforded 34.0 g of (7-bromo-3-nitroquinolin-4-yl)isobutylamine as yellow needles.
  • [0414] 1H NMR (300 MHz, CDCl3) δ 9.79 (brs, 1H), 9.35 (s, 1H), 8.16 (d, J=9.1 Hz, 1H), 8.16 (d, J=2.2 Hz, 1H), 7.57 (dd, J=9.1, 2.2 Hz, 1H), 3.75 (dd, J=6.6, 5.0 Hz, 2H), 2.14-2.01 (m, 1H), 1.10 (d, J=6.9 Hz, 6H).
  • Part F [0415]
  • A solution of Na[0416] 2S2O4 (193 g) in H2O (1 L) was added to a boiling solution of (7-bromo-3-nitroquinolin-4-yl)isobutylamine (32.0 g, 99 mmol) in isopropanol (1 L). Upon complete addition, the reaction mixture was cooled to room temperature and the bulk of the isopropanol was removed on a rotary evaporator. The resulting mixture was extracted with CH2Cl2 (3×), and the combined organic layers were dried over Na2SO4, filtered, and concentrated to afford 39.5 g of the crude 7-bromo—N4-isobutylquinoline-3,4-diamine as a yellow solid.
  • Part G [0417]
  • 7-Bromo-N[0418] 4-isobutylquinoline-3,4-diamine (39.4 g of crude material), trimethyl orthovalerate (32 g, 0.20 mol), and pyridine hydrochloride (0.31 g, 2.7 mmol) were combined with anhydrous toluene (500 mL) and heated to reflux for 30 min. The reaction was cooled to room temperature, concentrated, and the residue was purified by chromatography on silica gel (75% ethyl acetate in hexane to 100% ethyl acetate gradient) to afford 21.2 g of 7-bromo-2-butyl-1-isobutyl-1H-imidazo[4,5-c]quinoline as a yellow solid.
  • [0419] 1H NMR (300 MHz, CDCl3) δ 9.28 (s, 1H), 8.43 (d, J=2.2 Hz, 1H), 7.95 (d, J=8.7 Hz, 1H), 7.70 (dd, J=9.1, 2.2 Hz, 1H), 4.29 (d, J=7.5 Hz, 2H), 2.97-2.91 (m, 2H), 2.40-2.26 (m, 1H), 2.01-1.90 (m, 2H), 1.52 (sextet, J=7.5 Hz, 2H), 1.02 (d, J=6.9 Hz, 6H), 1.01 (t, J=7.3 Hz, 3H);
  • MS m/z (M+1[0420] +) calcd 362.1, obsd 362.1.
  • Part H [0421]
  • To a solution of 7-bromo-2-butyl-1-isobutyl-1H-imidazo[4,5-c]quinoline (10.8 g, 30.0 mmol) in CH[0422] 2Cl2 (300 mL) was added 3-chloroperoxybenzoic acid (10.4 g of approximately 77% purity). The reaction was allowed to stir overnight and was washed with 2M Na2CO3 (200 mL). The aqueous layer was extracted with CH2Cl2 (2×200 mL), and the combined organic layers were dried (MgSO4), filtered, and concentrated to afford 13.6 g orange solid. Recrystallization from boiling ethyl acetate (300 mL) afforded 8.25 g of 7-bromo-2-butyl-1-isobutyl-1H-imidazo[4,5-c]quinoline 5-oxide as a yellow powder.
  • [0423] 1H NMR (300 MHz, CDCl3) δ 9.24 (d, J=1.9 Hz, 1H), 9.00 (s, 1H), 7.93 (d, J=8.7 Hz, 1H), 7.81 (dd, J=9.1, 2.2 Hz, 1H), 4.26 (d, J=7.5 Hz, 2H), 2.94-2.89 (m, 2H), 2.37-2.23 (m, 1H), 1.97-1.87 (m, 2H), 1.51 (sextet, J=7.4 Hz, 2H), 1.03 (d, J=6.6 Hz, 6H), 1.01 (t, J=7.3 Hz, 3H);
  • MS m/z (M+1[0424] +) calcd 378.1, obsd 378.1.
  • Part I [0425]
  • To a vigorously stirred mixture of 7-bromo-2-butyl-1-isobutyl-1H-imidazo[4,5-c]quinoline 5-oxide (345 mg, 0.92 mmol) in CH[0426] 2Cl2 (7 mL) and NH4OH (0.50 mL of 30%) was added p-toluenesulfonyl chloride (175 mg, 0.92 mmol) in one portion. After 15 h, the reaction mixture was diluted with CH2Cl2 and washed with 2 M Na2CO3. The aqueous layer was extracted with CH2Cl2 (2×), and the combined organic layers were dried (Na2SO4), filtered, and concentrated to afford 331 mg of a yellow solid. Recrystallization from boiling isopropanol (3 mL) followed by purification on silica gel (40% acetone in toluene to 50% acetone in toluene gradient) afforded 208 mg of 7-bromo-2-butyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 198-200° C.
  • [0427] 1H NMR (300 MHz, CDCl3) δ 7.98 (d, J=2.2 Hz, 1H), 7.73 (d, J=8.7 Hz, 1H), 7.40 (dd, J=8.7, 1.9 Hz, 1H), 5.44 (s, 2H), 4.22 (d, J=7.8 Hz, 2H), 2.92-2.86 (m, 2H), 2.38-2.24 (m, 1H), 1.93-1.83 (m, 2H), 1.50 (sextet, J=7.5 Hz, 2H), 1.00 (d, J=6.9 Hz, 6H), 1.00 (t, J=7.3 Hz, 3H);
  • [0428] 13C NMR (75 MHz, CDCl3) δ 154.4, 152.0, 146.2, 133.3, 129.9, 127.2, 125.2, 121.1, 120.5, 114.6, 52.8, 30.3, 29.4, 27.7, 22.8, 20.0, 14.1;
  • MS m/z (M+1[0429] +) calcd 375.1, obsd 375.2;
  • Anal. Calcd for C[0430] 18H23BrN4: C, 57.60; H, 6.18; N, 14.93. Found: C, 57.54; H, 6.17; N, 14.98.
  • Part J [0431]
  • 7-Bromo-2-butyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine (751 mg, 2.00 mmol), thiophene-3-boronic acid (269 mg, 2.10 mmol), and n-propanol (3.6 mL) were combined in a reaction vessel and placed under an atmosphere of N[0432] 2. Pd(OAc)2 (1.3 mg, 0.0060 mmol), triphenylphosphine (4.7 mg, 0.018 mmol), Na2CO3 (1.2 mL of a 2 M solution, 2.4 mmol), and H2O (0.7 mL) were added, and the reaction mixture was heated to reflux in an oil bath for 2.5 h. Upon cooling to RT, the solid product was collected by filtration and washed with H2O and ethanol. Purification on silica gel (5%-6% methanol (MeOH) in CH2Cl2 gradient) afforded 700 mg of product which was recrystallized from boiling isopropanol (20 mL) to yield 535 mg of 2-butyl-1-isobutyl-7-(thiophen-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as an off-white powder, m.p. 229-230° C.
  • [0433] 1H NMR (300 MHz, CDCl3) δ 8.08 (d, J=1.9 Hz, 1H), 7.91 (d, J=8.7 Hz, 1H), 7.61-7.58 (m, 2H), 7.55 (dd, J=5.2, 1.4 Hz, 1H), 7.42 (dd, J=5.2, 3.0 Hz, 1H), 5.39 (s, 2H), 4.26 (d, J=7.5 Hz, 2H), 2.93-2.88 (m, 2H), 2.46-2.32 (m, 1H), 1.94-1.84 (m, 2H), 1.51 (sextet, J=7.4 Hz, 2H), 1.03 (d, J=6.6 Hz, 6H), 1.01 (t, J=7.5 Hz, 3H);
  • [0434] 13C NMR (75 MHz, CDCl3) δ 154.1, 151.7, 145.5, 142.3, 134.3, 133.6, 127.2, 126.53, 126.47, 124.6, 121.0, 120.6, 120.4, 114.8, 52.8, 30.4, 29.5, 27.8, 22.9, 20.0, 14.1;
  • MS m/z (M+1[0435] +) calcd 379.1956, obsd 379.1943;
  • Anal. Calcd for C[0436] 22H26N4S: C, 69.80; H, 6.92; N, 14.80; S, 8.47. Found: C, 69.45; H, 7.10; N, 14.90; S, 8.44.
  • Example 2 2-Butyl-1-isobutyl-7-phenyl-1H-imidazo[4,5-c]quinolin-4-amine
  • [0437]
    Figure US20040147543A1-20040729-C00048
  • 7-Bromo-2-butyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and benzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. Purification by chromatography on silica gel (20% acetone in toluene to 60% acetone in toluene gradient) afforded 2-butyl-1-isobutyl-7-phenyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. >250° C. [0438]
  • [0439] 1H NMR (300 MHz, CDCl3) δ 8.09 (d, J=1.9 Hz, 1H), 7.96 (d, J=8.7 Hz, 1H), 7.77-7.74 (m, 2H), 7.61 (dd, J=8.4, 1.9 Hz, 1H), 7.50-7.45 (m, 2H), 7.36 (tt, J=7.3, 1.5 Hz, 1H), 5.40 (s, 2H), 4.28 (d, J=7.5 Hz, 2H), 2.94-2.89 (m, 2H), 2.48-2.34 (m, 1H), 1.95-1.84 (m, 2H), 1.52 (sextet, J=7.4 Hz, 2H), 1.04 (d, J=6.6 Hz, 6H), 1.01 (t, J=7.3 Hz, 3H);
  • [0440] 13C NMR (75 MHz, CDCl3) δ 154.2, 151.7, 145.3, 141.0, 139.6, 133.6, 129.1, 127.6, 127.4, 127.2, 125.4, 121.6, 120.4, 114.9, 52.9, 30.4, 29.5, 27.8, 22.9, 20.0, 14.1;
  • MS m/z (M+1[0441] +) calcd 373.2, obsd 373.2;
  • Anal. Calcd for C[0442] 24H28N4: C, 77.38; H, 7.58; N, 15.04. Found: C, 77.16; H, 7.62; N, 14.95.
  • Example 3 2-Butyl-7-(2,4-dimethoxyphenyl)-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine
  • [0443]
    Figure US20040147543A1-20040729-C00049
  • 7-Bromo-2-butyl-1-isobutyl-1H-imidazo[4,5-c]quinoline and 2,4-dimethoxybenzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. The resulting 2-butyl-7-(2,4-dimethoxyphenyl)-1-isobutyl-1H-imidazo[4,5-c]quinoline was oxidized and then aminated according to the general procedures described in Parts H and I of Example 1 and purified by chromatography on silica gel (8% methanol in CH[0444] 2Cl2 to 10% methanol in CH2Cl2 gradient) followed by recrystallization from 1/1 ethyl acetate/hexane to afford 2-butyl-7-(2,4-dimethoxyphenyl)-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine as apale orange solid, m.p. 187-189° C.
  • [0445] 1H NMR (300 MHz, CDCl3) δ 7.96 (d, J=1.6 Hz, 1H), 7.89 (d, J=8.7 Hz, 1H), 7.53 (dd, J=8.4, 1.9 Hz, 1H), 7.40-7.37 (m, 1H), 6.62-6.58 (m, 2H), 5.38 (s, 2H), 4.25 (d, J=7.5 Hz, 2H), 3.87 (s, 3H), 3.83 (s, 3H), 2.93-2.88 (m, 2H), 2.50-2.36 (m, 1H), 1.94-1.84 (m, 2H), 1.51 (sextet, J=7.4 Hz, 2H), 1.02 (d, J=6.6 Hz, 6H), 1.01 (t, J=7.2 Hz, 3H);
  • [0446] 13C NMR (75 MHz, CDCl3) δ 160.6, 157.8, 152.9, 151.4, 145.0, 137.2, 133.6, 131.7, 127.7, 127.1, 124.3, 123.5, 119.3, 114.3, 105.0, 99.3, 55.8, 55.6, 52.8, 30.3, 29.4, 27.7, 22.9, 20.0, 14.1;
  • MS m/z (M+1[0447] +) calcd 433.2604, obsd 433.2600;
  • Anal. Calcd for C[0448] 26H32N4O2.0.17H2O: C, 71.67; H, 7.48; N, 12.86. Found: C, 71.25; H, 7.46; N, 12.81. Water content determined by Karl-Fischer analysis.
  • Example 4 2-Butyl-7-(4-tert-butylphenyl)-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine
  • [0449]
    Figure US20040147543A1-20040729-C00050
  • 7-Bromo-2-butyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and 4-tert-butylbenzeneboronic were coupled according to the general procedure described in Part J of Example 1. Purification by chromatography on silica gel (5% methanol in CH[0450] 2Cl2 to 6% methanol in CH2Cl2 gradient) followed by recrystallization from ethyl acetate afforded 2-butyl-7-(4-tert-butylphenyl)-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 219-220° C.
  • [0451] 1H NMR (300 MHz, CDCl3) δ 8.09 (d, J=1.9 Hz, 1H), 7.94 (d, J =8.7 Hz, 1H), 7.71 (dm, J=8.4 Hz, 2H), 7.60 (dd, J =8.6, 2.1 Hz, 1H), 7.51 (dm, J=8.7 Hz, 2H), 5.38 (s, 2H), 4.27 (d, J=7.5 Hz, 2H), 2.94-2.89 (m, 2H), 2.48-2.35 (m, 1H), 1.92-1.84 (m, 2H), 1.51 (sextet, J=7.4 Hz, 2H), 1.38 (s, 9H), 1.03 (d, J=6.6 Hz, 6H), 1.01 (t, J=7.3 Hz, 3H);
  • [0452] 13C NMR (100 MHz, CDCl3) δ 154.1, 151.6, 150.6, 145.4, 139.4, 138.0, 133.6, 127.1, 127.0, 126.0, 125.1, 121.5, 120.3, 114.8, 52.8, 34.8, 31.6, 30.4, 29.4, 27.8, 22.9, 20.0, 14.1;
  • MS m/z (M+1[0453] +) calcd 429.3, obsd 429.5;
  • Anal. Calcd for C[0454] 28H36N4: C, 78.46; H, 8.47; N, 13.07. Found: C, 78.10; H, 8.45; N, 13.02.
  • Example 5 2-Butyl-1-isobutyl-7-(4-propoxyphenyl)-1H-imidazo[4,5-c]quinolin-4-amine
  • [0455]
    Figure US20040147543A1-20040729-C00051
  • 7-Bromo-2-butyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and 4-propoxybenzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. The product was recrystallized from isopropanol, collected by filtration, dissolved in CH[0456] 2Cl2, and then precipitated with hexanes to afford 2-butyl-1-isobutyl-7-(4-propoxyphenyl)-1H-imidazo[4,5-c]quinolin-4-amine as a pale yellow solid, m.p. 194-197° C.
  • [0457] 1H NMR (300 MHz, CDCl3) δ 8.03 (d, J=1.9 Hz, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.69 (dm, J=8.7 Hz, 2H), 7.55 (dd, J=8.4, 1.9 Hz, 1H), 7.01 (dm, J=9.0 Hz, 2H), 5.42 (s, 2H), 4.25 (d, J=7.5 Hz, 2H), 3.98 (t, J=6.7 Hz, 2H), 2.93-2.88 (m, 2H), 2.40 (septet, J=6.9 Hz, 1H), 1.94-1.79 (m, 4H), 1.51 (sextet, J=7.4 Hz, 2H), 1.06 (t, J=7.5 Hz, 3H), 1.02 (d, J=7.2 Hz, 6H), 1.01 (t, J=7.5 Hz, 3H);
  • [0458] 13C NMR (75 MHz, CDCl3) δ 159.0, 154.0, 151.6, 145.5, 139.3, 133.6, 133.3, 128.3, 127.1, 124.8, 121.2, 120.3, 115.1, 114.5, 69.8, 52.8, 30.4, 29.4, 27.7, 22.87, 22.84, 20.0, 14.1, 10.8;
  • MS m/z (M+1[0459] +) calcd 431.2811, obsd 431.2821;
  • Anal. Calcd for C[0460] 27H34N4O: C, 75.31; H, 7.96; N, 13.01. Found: C, 75.20; H, 8.18; N, 12.96.
  • Example 6 2-Butyl-1-isobutyl-7-(2-propoxyphenyl)-1H-imidazo[4,5-c]quinolin-4-amine
  • [0461]
    Figure US20040147543A1-20040729-C00052
  • 7-Bromo-2-butyl-1-isobutyl-1 H-imidazo[4,5-c]quinolin-4-amine and 2-propoxybenzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. The product was recrystallized from isopropanol, collected by filtration, dissolved in CH[0462] 2Cl2, and then precipitated with hexanes to afford 2-butyl-1-isobutyl-7-(2-propoxyphenyl)-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, m.p. 174.5-176.0° C.
  • [0463] 1H NMR (300 MHz, CDCl3) δ 7.98 (d, J=1.9 Hz, 1H), 7.89 (d, J=8.7 Hz, 1H), 7.61 (dd, J=8.7, 1.9 Hz, 1H), 7.47 (dd, J=7.5, 1.9 Hz, 1H), 7.34-7.29 (m, 1H), 7.07-7.00 (m, 2H), 5.46 (s, 2H), 4.27 (d, J=7.5 Hz, 2H), 3.96 (t, J=6.6 Hz, 2H), 2.94-2.88 (m, 2H), 2.41 (septet, J=6.8 Hz, 1H), 1.94-1.84 (m, 2H), 1.76 (sextet, J=7.1 Hz, 2H), 1.51 (sextet, J=7.4 Hz, 2H), 1.03-0.93 (m, 12H);
  • [0464] 13C NMR (75 MHz, CDCl3) δ 156.4, 153.9, 151.4, 145.1, 137.6,133.6, 131.3, 131.0, 128.8, 127.9, 127.2, 124.5, 121.1, 118.9, 114.5, 113.0, 70.4, 52.8, 30.4, 29.4, 27.8, 22.9, 22.8, 20.0, 14.1, 10.9;
  • MS m/z (M+1[0465] +) calcd 431.2811, obsd 431.2809;
  • Anal. Calcd for C[0466] 27H34N4O.0.16H2O: C, 74.82; H, 7.98; N, 12.93. Found: C, 74.64; H, 7.99; N, 12.78. Water content determined by Karl-Fischer titration.
  • Example 7 2-Butyl-1-isobutyl-7-[(E)-2-phenylethenyl]-1H-imidazo[4,5-c]quinolin-4-amine
  • [0467]
    Figure US20040147543A1-20040729-C00053
  • 7-Bromo-2-butyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and trans-2-phenylvinylboronic acid were coupled according to the general procedure described in Part J of Example 1. Recrystallization from toluene followed by chromatography on silica gel (8% methanol in CH[0468] 2Cl2) afforded 2-butyl-1-isobutyl-7-[(E)-2-phenylethenyl]-1H-imidazo[4,5-c]quinolin-4-amine, m.p. 215-216° C.
  • [0469] 1H NMR (300 MHz, CDCl3) δ 7.92 (d, J=1.6 Hz, 1H), 7.87 (d, J =8.7 Hz, 1H), 7.57-7.52 (m, 3H), 7.40-7.35 (m, 2H), 7.30-7.24 (m, 3H), 5.44 (s, 2H), 4.24 (d, J=7.5 Hz, 2H), 2.93-2.87 (m, 2H), 2.37 (septet, J=6.9 Hz, 1H), 1.94-1.83 (m, 2H), 1.51 (sextet, J=7.4 Hz, 2H), 1.02 (d, J=7.2 Hz, 6H), 1.00 (t, J=7.5 Hz, 3H);
  • [0470] 1H NMR (500 MHz, CDCl3) δ 7.24 (center of AB pattern, J=16.4 Hz);
  • [0471] 13C NMR (100 MHz, CDCl3) δ 154.2, 151.6, 145.1, 137.6, 136.0, 133.6, 129.2, 128.9, 128.8, 127.9, 127.1, 126.8, 125.6, 120.5, 120.2, 115.1, 52.8, 30.4, 29.4, 27.7, 22.9, 20.0, 14.1;
  • MS m/z (M+1[0472] +) calcd 399.3, obsd 399.2;
  • Anal. Calcd for C[0473] 26H30N4: C, 78.36; H, 7.59; N, 14.06. Found: C, 78.05; H, 7.61; N, 14.01.
  • Example 8 2-Butyl-1-isobutyl-7-phenethyl-1H-imidazo[4,5-c]quinolin-4-amine
  • [0474]
    Figure US20040147543A1-20040729-C00054
  • 2-Butyl-1-isobutyl-7-[(E)-2-phenylethenyl]-1H-imidazo[4,5-c]quinolin-4-amine (562 mg, 1.41 mmol) was hydrogenated in a Parr bottle over palladium on carbon (10%) until the starting material was consumed as judged by high performance liquid chromatography (HPLC) and thin layer chromatography (TLC) analyses. Purification on silica (5% to 10% methanol in CH[0475] 2Cl2 gradient) followed by recrystallization from boiling CH3CN afforded 150 mg of 2-butyl-1-isobutyl-7-phenethyl-1H-imidazo[4,5-c]quinolin-4-amine, m.p. 181-182° C.
  • [0476] 1H NMR (300 MHz, CDCl3) δ 7.80 (d, J=8.4 Hz, 1H), 7.70 (d, J=1.6 Hz, 1H), 7.32-7.14 (m, 6H), 5.44 (s, 2H), 4.23 (d, J =7.5 Hz, 2H), 3.11-3.00 (m, 4H), 2.92-2.87 (m, 2H), 2.43-2.30 (m, 1H), 1.93-1.83 (m, 2H), 1.50 (sextet, J=7.4Hz, 2H), 1.00 (d, J =6.6 Hz, 6H), 1.00 (t, J=7.3 Hz, 3H);
  • [0477] 13C NMR (75 MHz, CDCl3) δ 153.9, 151.4, 145.1, 142.1, 140.8, 133.7, 128.7, 128.6, 126.8, 126.5, 126.1, 123.4, 119.8, 114.0, 52.8, 38.1, 38.0,30.4, 29.4,27.7, 22.9, 20.0, 14.1;
  • MS m/z (M+1[0478] +) calcd 401.2705, obsd 401.2705;
  • Anal. Calcd for C[0479] 26H32N4: C, 77.96; H, 8.05; N, 13.99. Found: C, 77.95; H, 8.02; N, 14.04.
  • Example 9 2-Ethoxymethyl-1-isobutyl-7-(thiophen-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine
  • [0480]
    Figure US20040147543A1-20040729-C00055
  • Part A [0481]
  • A solution of 7-bromo—N[0482] 4-isobutylquinoline-3,4-diamine (85 g, prepared according to Part F of Example 1) in anhydrous pyridine (413 mL) was immersed in an ice bath, and ethoxyacetyl chloride (36.9 g, 300 mmol) was added. The reaction was allowed to warm to room temperature and was then heated in an oil bath held at 85° C. for 3.5 h. The reaction mixture was concentrated under vacuum, and the residue was taken up in diethyl ether and washed with 2M Na2CO3 (2×) followed by H2O (1×). The organic layer was dried (MgSO4), filtered, and concentrated. Recrystallization of the resulting solid from boiling 15% ethyl acetate in hexanes afforded 43.0 g of 7-bromo-2-ethoxymethyl-1-isobutyl-1H-imidazo[4,5-c]quinoline as brown crystals.
  • [0483] 1H NMR (300 MHz, CDCl3) δ 9.28 (s, 1H), 8.45 (d, J=1.9 Hz, 1H), 7.99 (d, J=9.1 Hz, 1H), 7.74 (dd, J=8.7, 2.2 Hz, 1H), 4.88 (s, 2H), 4.49 (d, J=7.5 Hz, 2H), 3.61 (q, J=7.1 Hz, 2H), 2.45-2.31 (m, 1H), 1.24 (t, J=7.0 Hz, 3H), 1.01 (d, J=6.6 Hz, 6H);
  • MS m/z (M+1[0484] +) calcd 364.1, obsd 364.1.
  • Part B [0485]
  • 7-Bromo-2-ethoxymethyl-1-isobutyl-1H-imidazo[4,5-c]quinoline was oxidized and then aminated according to the general procedures described in Parts H and I of Example 1. Purification by recrystallization from isopropanol afforded 7-bromo-2-ethoxymethyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine as yellow needles. [0486]
  • [0487] 1H NMR (300 MHz, CDCl3) δ 7.96 (d, J =2.2 Hz, 1H), 7.73 (d, J=8.7 Hz, 1H), 7.39 (dd, J=8.7, 2.2 Hz, 1H), 5.80 (s, 2H), 4.80 (s, 2H), 4.38 (d, J=7.5 Hz, 2H), 3.60 (q, J=7.1 Hz, 2H), 2.42-2.28 (m, 1H), 1.24 (t, J=6.9 Hz, 3H), 0.99 (d, J=6.6 Hz, 6H);
  • [0488] 13C NMR (75 MHz, CDCl3) δ 152.4, 149.9, 146.5, 134.1, 129.8, 127.1, 125.3, 121.5, 121.1, 114.5, 66.5, 65.5, 53.1, 29.2, 20.0, 15.2;
  • Anal. Calcd for C[0489] 17H21BrN4O: C, 54.12; H, 5.61; N, 14.85. Found: C, 54.16; H, 5.61; N, 14.67.
  • Part C [0490]
  • 7-Bromo-2-ethoxymethyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and thiophene-3-boronic acid were coupled according to the general procedure described in Part J of Example 1. Recrystallization from isopropanol followed by purification on silica gel (5% methanol in CH[0491] 2Cl2 to 7% methanol in CH2Cl2 gradient) afforded 2-ethoxymethyl-1-isobutyl-7-(thiophen-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a pale yellow solid, m.p. 187-189° C.
  • [0492] 1H NMR (300 MHz, CDCl3) δ 8.08 (d, J=1.9 Hz, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.63-7.60 (m, 2H), 7.55 (dd, J=5.2,1.4 Hz, 1H), 7.43 (dd, J=5.2, 3.0 Hz, 1H), 5.44 (s, 2H), 4.83 (s, 2H), 4.45 (d, J =7.5 Hz, 2H), 3.61 (q, J=7.1 Hz, 2H), 2.44 (septet, J=6.8 Hz, 1H), 1.25 (t, J =7.0 Hz, 3H), 1.04 (d, J =6.9 Hz, 6H);
  • [0493] 13C NMR (125 MHz, CDCl3) δ 152.0,149.7, 145.8, 142.2, 134.9, 134.5, 127.1, 126.5, 124.6, 121.1, 120.84, 120.82, 114.8, 66.5, 65.6, 53.1, 29.3, 20.1, 15.3;
  • MS m/z (M+1[0494] +) calcd 381.1749, obsd 381.1763;
  • Anal. Calcd for C[0495] 21H24N4OS: C, 66.29; H, 6.36; N, 14.72. Found: C, 66.54; H, 6.37; N, 14.73.
  • Example 10 2-Butyl-1-(3-methanesulfonylpropyl)-7-phenyl-1H-imidazo[4,5-c]quinolin-4-amine
  • [0496]
    Figure US20040147543A1-20040729-C00056
  • Part A [0497]
  • A solution of 3-bromoaniline (344 g, 2.00 mol) and phenyl boronic acid (268 g, 2.2 mol) in n-propanol (3.5 L) was sparged with N[0498] 2 for 10 min. To this solution was added Pd(OAc)2 (1.35 g, 6.0 mmol), triphenylphosphine (4.72 g, 18.0 mmol), Na2CO3 (1.2 L of a 2 M solution, 2.4 mol), and H2O (700 mL). The reaction was brought to reflux under a N2 atmosphere over a period of 45 min and then cooled to RT and transferred to a separatory funnel. The clear aqueous layer was drawn off (1.1 L), and the organic layer was washed with brine (3×500 mL). The organic layer was treated with charcoal (90 g of Darco G-60) and MgSO4 (160 g) and was filtered through CELITE filter agent, washing with ethyl acetate. The filtrate was concentrated (420 g of an orange oil), dissolved in 1.1 L of 1/1 hexane/isopropanol, filtered to remove insoluble solid and then diluted with an additional 1.9 L of 1/1 hexane/isopropanol. The resulting solution was cooled in an ice bath and then anhydrous HCl in ether (1.05 L of a 2 M solution, 2.1 mol) was added. The solid was collected by filtration, washed with 700 mL diethyl ether (Et2O), and dried at RT in a vacuum oven to obtain 345 g of the HCl salt of biphenyl-3-ylamine as yellow crystals. The free base was obtained by shaking the solid with tert-butyl methyl ether and 1 N NaOH followed by isolation in the usual fashion.
  • [0499] 1H NMR (300 MHz, CDCl3): consistent with literature data (C. N. Carrigan et al., J. Med. Chem., 45, 2260-2276 (2002)).
  • Part B [0500]
  • Triethyl orthoformate (148 g, 1.00 mol), Meldrum's acid (137 g, 0.95 mol), and biphenyl-3-ylamine (155 g, 0.916 mol) were combined and treated according to the general procedure described in Part A of Example 1 to obtain 283 g of 5-(biphenyl-3-ylaminomethylene)-2,2-dimethyl-[1,3]dioxane-4,6-dione as a yellow solid. [0501]
  • [0502] 1H NMR (300 MHz, CDCl3) δ 11.33 (brd, J=14.0 Hz, 1H), 8.72 (d, J=15.0 Hz, 1H), 7.60-7.56 (m, 2H), 7.51-7.37 (m, 6H), 7.25-7.21 (m, 1H), 1.77 (s, 6H).
  • Part C [0503]
  • 5-(Biphenyl-3-ylaminomethylene)-2,2-dimethyl-[1,3]dioxane-4,6-dione (160.2 g, 496 mmol) was dissolved in 800 mL of DOWTHERM A heat transfer fluid at 100° C. and added over 40 min by way of a cannula line to 1.3 L of preheated DOWTHERM A heat transfer fluid to 215° C. After complete addition, the reaction was held at 215° C. for 90 min and then cooled to RT. The resulting solid was collected by filtration, sequentially washed with diethyl ether (1.7 L) and acetone (500 mL), and then dried in a vacuum oven at 70° C. overnight. The resulting product (74.5 g) contained approximately 5% of the undesired isomer. This product was combined with material from a separate run (51.4 g) and slurried in 440 mL of refluxing ethanol. Filtration of the slurry while hot followed by sequential ethanol and diethyl ether rinses afforded 106.1 g of 7-phenylquinolin-4-ol as a tan solid. [0504]
  • [0505] 1H NMR (300 MHz, d6-DMSO) δ 11.77 (brs, 1H), 8.16 (d, J=8.4 Hz, 1H), 7.95-7.91 (m, 1H), 7.75-7.70 (m, 3H), 7.61 (dd, J=8.4, 1.6 Hz, 1H), 7.56-7.50 (m, 2H), 7.47-7.42 (m, 1H), 6.05 (d, J=7.5 Hz, 1H).
  • Part D [0506]
  • A stirred suspension of 7-phenylquinolin-4-ol (84.9 g, 384 mmol) in propionic acid (850 mL) was heated to 129° C. Nitric acid (70%, 45.0 g) was added dropwise over 25 min, during which the temperature dropped to 124° C. The reaction was stirred an additional 3 h at that temperature and then cooled to 5° C. on an ice bath. The resulting solid was collected by filtration, washed with ice cold ethanol (until washings were nearly colorless) and dried at 70° C. in a vacuum oven overnight to obtain 83.2 g of 3-nitro-7-phenylquinolin-4-ol as a beige powder. [0507]
  • [0508] 1H NMR (300 MHz, d6-DMSO) δ 13.00 (brs, 1H), 9.23 (s, 1H), 8.33 (d, J =8.4 Hz, 1H), 7.94 (d, J =1.3 Hz, 1H), 7.83 (dd, J =8.4, 1.9 Hz, 1H), 7.77-7.74 (m, 2H), 7.59-7.53 (m, 2H), 7.51-7.45 (m, 1H);
  • MS m/z (M+1[0509] +) calcd 267.1, obsd 267.1.
  • Part E [0510]
  • A solution of phosphorous oxychloride (3.1 g, 20 mmol) in anhydrous N,N-dimethylformamide (DMF, 14 mL) was added to a suspension of 3-nitro-7-phenylquinolin-4-ol (5.0 g, 18.8 mmol) in 80 mL of DMF over 3 min. The reaction was allowed to stir for 1.5 h and then poured into 250 mL crushed ice. The resulting precipitate was collected by filtration, washed with H[0511] 2O, and dried under vacuum for 2 h. The crude 4-chloro-3-nitro-7-phenylquinoline thus obtained was used without further purification.
  • Part F [0512]
  • 4—Chloro-3-nitro-7-phenylquinoline (5.3 g, 18.8 mmol) and 3-methylsulfanyl-propylamine (2.17 g, 20.6 mmol) were combined and treated according to the general procedure described in Part E of Example 1. Recrystallization from isopropanol afforded 6.2 g of (3-methylsulfanylpropyl)- (3-nitro-7-phenylquinolin-4-yl)amine as gold plates. [0513]
  • Part G [0514]
  • (3-Methylsulfanylpropyl)-(3-nitro-7-phenylquinolin-4-yl)amine (3.0 g, 8.5 mmol) was hydrogenated in a Parr bottle over Pt/C (0.3 g of 5%) in 42 mL of toluene for 1 h. The reaction mixture was filtered through CELITE filter agent, washed with methanol (100 mL) and CHCl[0515] 3 (50 mL), and then concentrated to afford 2.75 g of N4-(3-methylsulfanylpropyl)-7-phenylquinoline-3,4-diamine as a brown oil.
  • Part H [0516]
  • N[0517] 4-(3-Methylsulfanylpropyl)-7-phenylquinoline-3,4-diamine (2.75 g, 8.49 mmol), trimethyl orthovalerate (1.7 g, 10 mmol), and pyridine hydrochloride (0.3 g) were dissolved in toluene (28 mL) and heated to reflux for 1.5 h, collecting the volatiles in a Dean—Stark trap. Upon cooling to room temperature, the solvent was removed under vacuum. The resulting solid was slurried in hexanes (100 mL) for 1 h and then collected by filtration to afford 3.0 g of 2-butyl-1-(3-methylsulfanylpropyl)-7-phenyl-1H-imidazo[4,5-c]quinoline.
  • Part I [0518]
  • To a solution of 2-butyl-1-(3-methylsulfanylpropyl)-7-phenyl-1H-imidazo[4,5-c]quinoline (3.0 g, 7.70 mmol) in CHCl[0519] 3 (39 mL) was added 3-chloroperoxybenzoic acid (6.74 g of approximately 77% purity) over 20 min. Aqueous NH4OH (39 mL, 30%) was added, and to the resulting rapidly stirred biphasic suspension was addedp-toluenesulfonyl chloride (1.8 g, 9.44 mmol) in one portion. After monitoring by thin layer chromatography indicated that no starting material remained, the reaction mixture was sequentially washed with 1% Na2CO3 (2×50 mL) and brine (50 mL); then dried (Na2SO4); filtered; and concentrated to a brown solid. Purification on silica (5% methanol in CH2Cl2) followed by recrystallization from CH3CN afforded 0.50 g of 2-butyl-1-(3-methanesulfonylpropyl)-7-phenyl-1H-imidazo[4,5-c]quinolin-4-amine as colorless needles, m.p. 214-216° C.
  • [0520] 1H NMR (300 MHz, d6-DMSO) δ 8.21 (d, J=8.7 Hz, 1H), 7.87 (d, J=1.9 Hz, 1H), 7.78-7.75 (m, 2H), 7.57-7.48 (m, 3H), 7.41-7.36 (m, 1H), 6.52 (s, 2H), 4.69 (t, J=7.5 Hz, 2H), 3.41 (t, J=7.6 Hz, 2H), 3.02 (s, 3H), 2.95 (t, J=7.8 Hz, 2H), 2.30-2.20 (m, 2H), 1.82 (pentet, J=7.6 Hz, 2H), 1.47 (sextet, J=7.5 Hz, 2H), 0.97 (t, J=7.3 Hz, 3H);
  • MS m/z (M+1[0521] +) calcd 437.2, obsd 437.3;
  • Anal. Calcd for C[0522] 24H28N4O2S: C, 66.03; H, 6.46; N, 12.86. Found: C, 66.09; H, 6.43; N, 12.57.
  • Example 11 8-(4-tert-Butylphenyl)-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine
  • [0523]
    Figure US20040147543A1-20040729-C00057
  • Part A [0524]
  • To a solution of 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine (10.0 g, 41.6 mmol) in acetic acid (150 mL) was added Br[0525] 2 (10.0 g, 62.6 mmol), and after 24 h, the resulting solid was collected by filtration and washed with H2O. The orange solid was suspended in a saturated aqueous solution of NaHSO3, after which it was again collected and stirred with a 2 M solution of Na2CO3 for 18 h. The solid was collected by filtration, washed with H2O, and azeotropically dried with toluene on a rotary evaporator. Purification on silica gel (7%-10% methanol in CH2Cl2 gradient) afforded 3.4 g of 8-bromo-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine.
  • [0526] 1H NMR (400 MHz, CDCl3) 6 8.00 (d, J=2.2 Hz, 1H), 7.79 (s, 1H), 7.69 (d, J=9.0 Hz, 1H), 7.59 (dd, J=8.8, 2.2 Hz, 1H), 5.60 (s, 2H), 4.26 (d, J=7.4 Hz, 2H), 2.37-2.27 (m, 1H), 1.05 (d, J=6.6 Hz, 6H).
  • Part B [0527]
  • 8-Bromo-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and 4-tert-butylbenzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. Recrystallization from isopropanol followed by chromatography on silica gel (7% methanol in CH[0528] 2Cl2) afforded 8-(4-tert-butylphenyl)-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. >250° C.
  • [0529] 1H NMR (400 MHz, d6-DMSO) δ 8.21 (s, 1H), 8.16 (d, J=2.0 Hz, 1H), 7.75 (dd, J=8.8, 2.1 Hz, 1H), 7.70-7.67 (m, 3H), 7.52 (dt, J=8.6, 2.1 Hz, 2H), 6.68 (s, 2H), 4.49 (d, J=7.2 Hz, 2H), 2.28 (septet, J=6.8 Hz, 1H), 1.33 (s, 9H), 0.97 (d, J=6.6 Hz, 6H);
  • [0530] 13C NMR (125 MHz, d6-DMSO) δ 152.2,149.4, 144.3, 143.4, 137.6, 132.7, 131.7, 128.5, 126.7, 126.2, 125.8, 125.5, 118.0, 115.1, 53.5,34.2,31.1, 28.5, 19.4;
  • Anal. Calcd for C[0531] 24H28N4: C, 77.38; H, 7.58; N, 15.04. Found: C, 77.17; H, 7.57; N, 14.99.
  • Example 12 1-Isobutyl-8-(thiophen-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine
  • [0532]
    Figure US20040147543A1-20040729-C00058
  • 8-Bromo-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and thiophene-3-boronic acid were coupled according to the general procedure described in Part J of Example 1. Recrystallization from isopropanol followed by chromatography on silica gel (7% methanol in CH[0533] 2Cl2) afforded 1-isobutyl-8-(thiophen-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 235-236° C.
  • [0534] 1H NMR (400 MHz, d6-DMSO) δ 8.20 (s, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.88 (dd, J=3.0, 1.4 Hz, 1H), 7.81 (dd, J=8.7, 2.0 Hz, 1H), 7.70 (dd, J=5.1, 3.0 Hz, 1H), 7.64-7.62 (m, 2H), 6.66 (s, 2H), 4.51 (d, J=7.4 Hz, 2H), 2.23 (septet, J=6.9 Hz, 1H), 0.96 (d, J=6.6 Hz, 6H);
  • [0535] 13C NMR (125 MHz, d6-DMSO) δ 152.1, 144.2, 143.4, 141.8, 131.7, 128.5, 128.1, 127.2, 126.6, 126.1, 125.3, 119.9, 117.5, 115.0, 53.5, 28.4, 19.4;
  • Anal. Calcd for C[0536] 18H18N4S: C, 67.05; H, 5.63; N, 17.38. Found: C, 66.74; H, 5.46; N, 17.32.
  • Example 13 8-(2,4-Dimethoxyphenyl)-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine
  • [0537]
    Figure US20040147543A1-20040729-C00059
  • 8-Bromo-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and 2,4-dimethoxybenzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. Purification by chromatography on silica gel (7% methanol in CH[0538] 2Cl2) afforded 8-(2,4-dimethoxyphenyl)-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 223-227° C.
  • [0539] 1H NMR (400 MHz, d6-DMSO) δ 8.18 (s, 1H), 8.08 (d, J=2.0 Hz, 1H), 7.62 (d, J=8.6 Hz, 1H), 7.52 (dd, J=8.6, 2.0 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 6.71 (d, J=2.4 Hz, 1H), 6.66 (dd, J=8.3, 2.4 Hz, 1H), 6.61 (s, 2H), 4.36 (d, J=7.5 Hz, 2H), 3.82 (s, 3H), 3.80 (s, 3H), 2.34-2.24 (m, 1H), 0.93 (d, J=6.6 Hz, 6H);
  • [0540] 13C NMR (100 MHz, d6-DMSO) δ 159.8, 157.1, 152.0, 143.6, 143.2, 131.7, 130.9, 130.5, 128.3, 128.1, 125.7, 122.5, 120.8, 114.4, 105.4, 99.0, 55.6, 55.3, 55.4, 28.2, 19.3;
  • Anal. Calcd for C[0541] 22H24N4O2: C, 70.19; H, 6.43; N, 14.88. Found: C, 69.92; H, 6.41; N, 14.67.
  • Example 14 1-Isobutyl-8-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine
  • [0542]
    Figure US20040147543A1-20040729-C00060
  • 8-Bromo-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and pyridine-3-boronic acid were coupled according to the general procedure described in Part J of Example 1. Purification by chromatography on silica gel (7%-10% methanol in CH[0543] 2Cl2 gradient) afforded 1-isobutyl-8-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 244-246° C.
  • [0544] 1H NMR (400 MHz, d6-DMSO) δ 9.01 (dd, J=2.3,0.8 Hz, 1H), 8.57 (dd, J=4.7, 1.6 Hz, 1H), 8.22 (s, 1H), 8.22 (d, J=2.0 Hz, 1H), 8.18 (ddd, J=8.0, 2.5, 1.6 Hz, 1H), 7.82 (dd, J=8.7, 2.1 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.52 (ddd, J=8.0, 4.7, 0.8 Hz, 1H), 6.76 (s, 2H), 4.52 (d, J=7.2 Hz, 2H), 2.29-2.22 (m, 1H), 0.95 (d, J=6.6 Hz, 6H);
  • [0545] 13C NMR (125 MHz, d6-DMSO) δ 152.5, 147.9, 147.6, 144.8, 143.5, 135.9, 133.8, 131.7, 129.5, 128.5, 126.9, 125.5, 123.9, 118.7, 115.2, 53.4, 28.4, 19.4;
  • Anal. Calcd for C[0546] 19H19N5: C, 71.90; H, 6.03; N, 22.07. Found: C, 71.73; H, 5.91; N, 21.86.
  • Example 15 1-Isobutyl-8-phenyl-1H-imidazo[4,5-c]quinolin-4-amine
  • [0547]
    Figure US20040147543A1-20040729-C00061
  • 8-Bromo-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and benzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. Recrystallization from isopropanol followed by recrystallization from methanol afforded 1-isobutyl-8-phenyl-1H-imidazo[4,5-c]quinolin-4-amine as a beige solid, m.p. 203-204° C. [0548]
  • [0549] 1H NMR (400 MHz, d6-DMSO) δ 8.21 (s, 1H), 8.17 (d, J=2.0 Hz, 1H), 7.78-7.76 (m, 3H), 7.69 (d, J=8.6 Hz, 1H), 7.52-7.48 (m, 2H), 7.36 (tt, J=7.4, 1.2 Hz, 1H), 6.71 (s, 2H), 4.49 (d, J=7.4 Hz, 2H), 2.32-2.21 (m, 1H), 0.96 (d, J=6.6 Hz, 6H);
  • [0550] 13C NMR (100 MHz, d6-DMSO) δ 152.3, 144.4, 143.4, 140.5, 132.8, 131.8, 129.0, 128.5, 126.9, 126.7, 126.5, 125.6, 118.4, 115.1, 53.6, 28.5, 19.4;
  • Anal. Calcd for C[0551] 20H20N4: C, 75.92; H, 6.37; N, 17.71. Found: C, 75.80; H, 6.26; N, 17.68.
  • Example 16 2-Ethyl-1-isobutyl-8-phenyl-1H-imidazo[4,5-c]quinolin-4-amine
  • [0552]
    Figure US20040147543A1-20040729-C00062
  • Part A [0553]
  • To a solution of 2-ethyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine (805 mg, 3.00 mmol) in acetic acid (10 mL) was added Br[0554] 2 (719 mg, 4.50 mmol), and after 20 h, the resulting solid was collected by filtration and washed with H2O. The orange solid was suspended in NaHSO3 (25 mL of a saturated solution) and stirred for 23 h, after which it was again collected and stirred with NaHCO3 (20 mL of a saturated solution) and CH2Cl2. The organic layer was drawn off, washed with H2O, dried (Na2SO4), filtered, and concentrated to afford 858 mg of a yellow solid. Purification on silica gel (5%-7% MeOH in CH2Cl2 gradient) afforded 450 mg of 8-bromo-2-ethyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine as a yellow solid. Additional purification on silica as before followed by recrystallization from boiling isopropanol (10 mL) afforded 316 mg of white needles, m.p. 222-223° C.
  • [0555] 1H NMR (400 MHz, d6-DMSO) δ 8.02 (s, 1H), 7.52 (s, 2H), 6.65 (s, 2H), 4.33 (d, J=7.0 Hz, 2H), 2.94 (q, J=7.5 Hz, 2H), 2.18-2.07 (m, 1H), 1.37 (t, J=7.5 Hz, 3H), 0.94 (d, J=6.8 Hz, 6H);
  • [0556] 13C NMR (100 MHz, d6-DMSO) δ 155.1, 152.1, 143.6, 131.4, 128.9, 128.3, 127.0, 122.3, 116.2, 112.8, 51.3, 28.9, 20.2, 19.2, 12.1;
  • Anal. Calcd for C[0557] 16H19BrN4: C, 55.34; H, 5.52; N, 16.13. Found: C, 55.26; H, 5.36; N, 16.14.
  • Part B [0558]
  • 8-Bromo-2-ethyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and benzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. Chromatography on silica gel (5%-7% methanol in CH[0559] 2Cl2 gradient) afforded 2-ethyl-1-isobutyl-8-phenyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 233-235° C.
  • [0560] 1H NMR (400 MHz, d6-DMSO) δ 8.15 (d, J=1.8 Hz, 1H), 7.77-7.72 (m, 3H), 7.68 (d, J=8.6 Hz, 1H), 7.52-7.48 (m, 2H), 7.36 (tt, J=7.4, 1.1 Hz, 1H), 6.57 (s, 2H), 4.42 (d, J=6.6 Hz, 2H), 2.96 (q, J=7.5 Hz, 2H), 2.35-2.24 (m, 1H), 1.39 (t, J=7.5 Hz, 3H), 0.98 (d, J=6.6 Hz, 6H);
  • [0561] 13C NMR (100 MHz, d6-DMSO) δ 154.6, 151.9, 144.2, 140.7, 132.7, 132.5, 129.0, 126.9, 126.8, 126.6, 125.1, 118.2, 115.1, 51.5, 28.9, 20.2, 19.3, 12.1;
  • Anal. Calcd for C[0562] 22H24N4: C, 76.71; H, 7.02; N, 16.27. Found: C, 76.52; H, 6.89; N, 16.30.
  • Example 17 2-Ethyl-1-isobutyl-8-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine
  • [0563]
    Figure US20040147543A1-20040729-C00063
  • 8-Bromo-2-ethyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and pyridine-3-boronic acid were coupled according to the general procedure described in Part J of Example 1. Chromatography on silica gel (5%-7% methanol in CH[0564] 2Cl2 gradient) followed by recrystallization from isopropanol afforded 2-ethyl-1-isobutyl-8-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as white crystals, m.p. >250° C.
  • [0565] 1H NMR (400 MHz, d6-DMSO) δ 9.00 (d, J=2.4 Hz, 1H), 8.57 (dd, J=4.8, 1.5 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 8.16 (dt, J=7.9, 1.7 Hz, 1H), 7.78 (dd, J=8.6, 2.0 Hz, 1H), 7.71 (d, J=8.6 Hz, 1H), 7.53 (dd, J=7.9, 4.8 Hz, 1H), 6.63 (s, 2H), 4.45 (d, J=6.8 Hz, 2H), 2.96 (q, J=7.5 Hz, 2H), 2.33-2.23 (m, 1H), 1.39 (t, J=7.5 Hz, 3H), 0.96 (d, J=6.4 Hz, 6H);
  • [0566] 13C NMR (100 MHz, d6-DMSO) δ 154.7, 152.2, 147.9, 147.6, 144.7, 136.1, 133.9, 132.4, 129.4, 127.0, 126.9, 125.1, 124.0, 118.6, 115.2, 51.4, 28.9, 20.3, 19.3, 12.1;
  • Anal. Calcd for C[0567] 21H23N5: C, 73.02; H, 6.71; N, 20.27. Found: C, 73.24; H, 6.77; N, 20.65.
  • Example 18 1-Butyl-2-ethoxymethyl-8-phenyl-1H-imidazo[4,5-c]quinolin-4-amine
  • [0568]
    Figure US20040147543A1-20040729-C00064
  • Part A [0569]
  • 1-Butyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine was brominated according to the general procedure described in Part A of Example 11. Purification on silica gel (6%-10% methanol in CH[0570] 2Cl2) followed by recrystallization from isopropanol afforded 8-bromo-1-butyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine as yellow needles, m.p. 182-183° C.
  • [0571] 1H NMR (300 MHz, CDCl3) δ 8.07 (d, J=2.2 Hz, 1H), 7.68 (d, J=8.7 Hz, 1H), 7.58 (dd, J=8.7, 2.2 Hz, 1H), 5.44 (s, 2H), 4.80 (s, 2H), 4.56-4.51 (m, 2H), 3.61 (q, J=7.0 Hz, 2H), 2.02-1.93 (m, 2H), 1.57 (sextet, J=7.4 Hz, 2H), 1.25 (t, J=6.9 Hz, 3H), 1.07 (t, J=7.3 Hz, 3H);
  • [0572] 13C NMR (75 MHz, CDCl3) δ 151.8, 149.7, 144.0, 133.3, 130.6, 129.1, 127.3, 122.7, 117.0, 115.5, 66.6, 65.4, 46.2, 32.3, 20.3, 15.3, 13.9;
  • MS m/z (M+1[0573] +) calcd 379.1, obsd 379.0;
  • Anal. Calcd for C[0574] 17H21BrN4O: C, 54.12; H, 5.61; N, 14.85. Found: C, 54.01; H, 5.50; N, 14.83.
  • Part B [0575]
  • 8-Bromo-1-butyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine and benzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. Chromatography on silica gel (10% methanol in CH[0576] 2Cl2) followed by recrystallization from isopropanol afforded 1-butyl-2-ethoxymethyl-8-phenyl-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid, m.p. 186-187° C.
  • [0577] 1H NMR (300 MHz, CDCl3) δ 8.17 (d, J=1.9 Hz, 1H), 7.89 (d, J=8.7 Hz, 1H), 7.79 (dd, J=8.7, 1.9 Hz, 1H), 7.69-7.66 (m, 2H), 7.52-7.47 (m, 2H), 7.37 (tt, J=7.3, 1.3 Hz, 1H), 5.46 (s, 2H), 4.82 (s, 2H), 4.64-4.58 (m, 2H), 3.62 (q, J=7.0 Hz, 2H), 2.11-2.01 (m, 2H), 1.58 (sextet, J=7.5 Hz, 2H), 1.26 (t, J=7.0 Hz, 3H), 1.05 (t, J=7.3 Hz, 3H);
  • [0578] 13C NMR (75 MHz, CDCl3) δ 151.7, 149.2, 144.7, 141.5, 135.4, 134.5, 129.1, 127.8, 127.3, 127.2, 126.9, 118.5, 115.9, 66.5, 65.4, 46.4, 32.5, 20.4, 15.3, 13.9;
  • MS m/z (M+1[0579] +) calcd 375.2, obsd 375.2;
  • Anal. Calcd for C[0580] 23H26N4O: C, 73.77; H, 7.00; N, 14.96. Found: C, 73.76; H, 7.15; N, 14.95.
  • Example 19 1-Butyl-2-ethoxymethyl-8-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine
  • [0581]
    Figure US20040147543A1-20040729-C00065
  • 8-Bromo-1-butyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine and pyridine-3-boronic acid were coupled according to the general procedure described in Part J of Example 1. Chromatography on silica gel (8%-10% methanol in CH[0582] 2Cl2 gradient) followed by recrystallization from isopropanol (3×) and chromatography as above afforded 1-butyl-2-ethoxymethyl-8-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 220-222° C.
  • [0583] 1H NMR (300 MHz, CDCl3) δ 8.95 (dd, J=2.3, 0.8 Hz, 1H), 8.63 (dd, J=4.7, 1.6 Hz, 1H), 8.17 (d, J=2.2 Hz, 1H), 7.96 (ddd, J=7.8, 2.5, 1.6 Hz, 1H), 7.92 (d, J=8.7 Hz, 1H), 7.76 (dd, J=8.7, 1.9 Hz, 1H), 7.42 (ddd, J=8.0, 4.8, 0.8 Hz, 1H), 5.47 (s, 2H), 4.83 (s, 2H), 4.65-4.60 (m, 2H), 3.63 (q, J=7.0 Hz, 2H), 2.10-1.99 (m, 2H), 1.57 (sextet, J=7.5 Hz, 2H), 1.26 (t, J=7.0 Hz, 3H), 1.04 (t, J=7.3 Hz, 3H);
  • [0584] 13C NMR (125 MHz, CDCl3) δ 152.0, 149.5, 148.49, 148.51, 145.2, 137.0, 134.4, 134.3, 131.8, 128.3, 127.4, 126.6, 123.9, 118.7, 116.2, 66.6, 65.4, 46.5, 32.5, 20.4, 15.3, 14.0;
  • MS m/z (M+1[0585] +) calcd 376.2, obsd 376.2;
  • Anal. Calcd for C[0586] 22H25N5O: C, 70.37; H, 6.71; N, 18.66. Found: C, 70.00; H, 6.49; N, 18.64.
  • Examples 20-65
  • The compounds in the table below were prepared according to the following method. 8-Bromo-1-isobutyl-1H-imidazo[4,5-c]quinoline-4-amine (25 mg) was dissolved in 1:1 volume:volume (v:v) dichloromethane:methanol. An aliquot (2 mL, 1.0 equivalents (eq.)) was placed in a 2 dram (7.4 mL) vial. The solvent was removed by vacuum centrifugation. The vial was charged with the appropriate boronic acid (1.25 eq.), palladium (II) acetate (0.1 eq.), and n-propanol (900 μL) and then sonicated for 30 seconds. The vial was then charged with 2M aqueous sodium carbonate solution (313 μL), deionized water (63 μL), and a solution of triphenylphosphine in n-propanol (63 μL, 0.15 eq.). The vial was capped and then heated to 80° C. for 5 hours in a sand bath. The vial was allowed to cool to room temperature and then the solvent was removed by vacuum centrifugation. The residue was purified by preparative high performance liquid chromatography using the method described above to provide the trifluoroacetate salt of the desired compound. The table below shows the structure of the free base and the measured mass (M+H). [0587]
    Figure US20040147543A1-20040729-C00066
    Measured Mass
    Example Number R3 (M + H)
    20
    Figure US20040147543A1-20040729-C00067
    317.1774
    21
    Figure US20040147543A1-20040729-C00068
    323.1330
    22
    Figure US20040147543A1-20040729-C00069
    331.1920
    23
    Figure US20040147543A1-20040729-C00070
    331.1905
    24
    Figure US20040147543A1-20040729-C00071
    331.1945
    25
    Figure US20040147543A1-20040729-C00072
    332.1877
    26
    Figure US20040147543A1-20040729-C00073
    335.1661
    27
    Figure US20040147543A1-20040729-C00074
    335.1678
    28
    Figure US20040147543A1-20040729-C00075
    335.1677
    29
    Figure US20040147543A1-20040729-C00076
    343.1921
    30
    Figure US20040147543A1-20040729-C00077
    345.2095
    31
    Figure US20040147543A1-20040729-C00078
    345.2093
    32
    Figure US20040147543A1-20040729-C00079
    345.2099
    33
    Figure US20040147543A1-20040729-C00080
    347.1888
    34
    Figure US20040147543A1-20040729-C00081
    347.1874
    35
    Figure US20040147543A1-20040729-C00082
    347.1892
    36
    Figure US20040147543A1-20040729-C00083
    347.1865
    37
    Figure US20040147543A1-20040729-C00084
    351.1367
    38
    Figure US20040147543A1-20040729-C00085
    351.1375
    39
    Figure US20040147543A1-20040729-C00086
    351.1375
    40
    Figure US20040147543A1-20040729-C00087
    353.1594
    41
    Figure US20040147543A1-20040729-C00088
    353.1577
    42
    Figure US20040147543A1-20040729-C00089
    353.1579
    43
    Figure US20040147543A1-20040729-C00090
    353.1587
    44
    Figure US20040147543A1-20040729-C00091
    357.1731
    45
    Figure US20040147543A1-20040729-C00092
    359.1873
    46
    Figure US20040147543A1-20040729-C00093
    361.1670
    47
    Figure US20040147543A1-20040729-C00094
    361.1639
    48
    Figure US20040147543A1-20040729-C00095
    363.1652
    49
    Figure US20040147543A1-20040729-C00096
    367.1932
    50
    Figure US20040147543A1-20040729-C00097
    367.1942
    51
    Figure US20040147543A1-20040729-C00098
    369.1288
    52
    Figure US20040147543A1-20040729-C00099
    373.1484
    53
    Figure US20040147543A1-20040729-C00100
    373.1494
    54
    Figure US20040147543A1-20040729-C00101
    374.1965
    55
    Figure US20040147543A1-20040729-C00102
    377.1985
    56
    Figure US20040147543A1-20040729-C00103
    377.2000
    57
    Figure US20040147543A1-20040729-C00104
    381.1507
    58
    Figure US20040147543A1-20040729-C00105
    385.1658
    59
    Figure US20040147543A1-20040729-C00106
    385.0974
    60
    Figure US20040147543A1-20040729-C00107
    385.0998
    61
    Figure US20040147543A1-20040729-C00108
    385.0982
    62
    Figure US20040147543A1-20040729-C00109
    389.1980
    63
    Figure US20040147543A1-20040729-C00110
    393.2057
    64
    Figure US20040147543A1-20040729-C00111
    401.1596
    65
    Figure US20040147543A1-20040729-C00112
    409.2036
  • Examples 66-105
  • The compounds in the table below were prepared according to the method of Examples 20-65 above using 7-bromo-2-butyl-1-isobutyl-1H-imidazo[4,5c]quinoline-4-amine as the starting material. The table below shows the structure of the free base and the measured mass (M+H). [0588]
    Figure US20040147543A1-20040729-C00113
    Measured Mass
    Example Number R3 (M + H)
    66
    Figure US20040147543A1-20040729-C00114
    373.2385
    67
    Figure US20040147543A1-20040729-C00115
    379.1978
    68
    Figure US20040147543A1-20040729-C00116
    387.2582
    69
    Figure US20040147543A1-20040729-C00117
    387.2550
    70
    Figure US20040147543A1-20040729-C00118
    387.2545
    71
    Figure US20040147543A1-20040729-C00119
    388.2536
    72
    Figure US20040147543A1-20040729-C00120
    399.2577
    73
    Figure US20040147543A1-20040729-C00121
    401.2712
    74
    Figure US20040147543A1-20040729-C00122
    401.2686
    75
    Figure US20040147543A1-20040729-C00123
    401.2719
    76
    Figure US20040147543A1-20040729-C00124
    403.2483
    77
    Figure US20040147543A1-20040729-C00125
    403.2507
    78
    Figure US20040147543A1-20040729-C00126
    403.2516
    79
    Figure US20040147543A1-20040729-C00127
    403.2505
    80
    Figure US20040147543A1-20040729-C00128
    407.2021
    81
    Figure US20040147543A1-20040729-C00129
    407.2024
    82
    Figure US20040147543A1-20040729-C00130
    407.2008
    83
    Figure US20040147543A1-20040729-C00131
    409.2214
    84
    Figure US20040147543A1-20040729-C00132
    409.2227
    85
    Figure US20040147543A1-20040729-C00133
    409.2241
    86
    Figure US20040147543A1-20040729-C00134
    413.2376
    87
    Figure US20040147543A1-20040729-C00135
    417.2313
    88
    Figure US20040147543A1-20040729-C00136
    418.2268
    89
    Figure US20040147543A1-20040729-C00137
    419.2299
    90
    Figure US20040147543A1-20040729-C00138
    419.2283
    91
    Figure US20040147543A1-20040729-C00139
    423.2552
    92
    Figure US20040147543A1-20040729-C00140
    423.2559
    93
    Figure US20040147543A1-20040729-C00141
    425.1915
    94
    Figure US20040147543A1-20040729-C00142
    429.2125
    95
    Figure US20040147543A1-20040729-C00143
    429.2142
    96
    Figure US20040147543A1-20040729-C00144
    433.2633
    97
    Figure US20040147543A1-20040729-C00145
    433.2613
    98
    Figure US20040147543A1-20040729-C00146
    437.2122
    99
    Figure US20040147543A1-20040729-C00147
    441.2265
    100
    Figure US20040147543A1-20040729-C00148
    441.1620
    101
    Figure US20040147543A1-20040729-C00149
    441.1646
    102
    Figure US20040147543A1-20040729-C00150
    441.1586
    103
    Figure US20040147543A1-20040729-C00151
    449.2728
    104
    Figure US20040147543A1-20040729-C00152
    457.2203
    105
    Figure US20040147543A1-20040729-C00153
    465.2656
  • Examples 106-116
  • 7-Bromo-2-ethoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine and the boronic acid or boronic acid ester from the table below were coupled according to the general procedure described in Part J of Example 1. The reaction was heated at reflux overnight unless otherwise indicated below the table. The solid collected from the reaction was washed with hexanes. Samples that were recrystallized from isopropanol and then dichloromethane:hexanes were dried under high vacuum overnight. Samples that were recrystallized from acetonitrile were then washed with hexanes and dried overnight in a vacuum oven at 75-80° C. The purification for Examples 115 and 1 16 is described below the table. [0589]
    Figure US20040147543A1-20040729-C00154
    Recrystallization
    Example Boronic Acid or Ester Solvent R3
    106 3-Propoxyphenylboronic acid Isopropanol then dichloromethane: hexanes
    Figure US20040147543A1-20040729-C00155
    107 4-Propoxyphenylboronic acid Isopropanol then dichloromethane: hexanes
    Figure US20040147543A1-20040729-C00156
    108 Phenylboronic acid Isopropanol then dichloromethane: hexanes
    Figure US20040147543A1-20040729-C00157
    109 2-Propoxyphenylboronic acid Isopropanol, then acetonitrile
    Figure US20040147543A1-20040729-C00158
    110 4-Cyanophenylboronic acid Acetonitrile
    Figure US20040147543A1-20040729-C00159
    111 3-Cyanophenylboronic acid Acetonitrile
    Figure US20040147543A1-20040729-C00160
    112 trans-2-[4- (Trifluoromethyl)phenyl]vinylboronic acid Acetonitrile
    Figure US20040147543A1-20040729-C00161
    113 Pyridine-3-boronic acid 1,3- propanediol cyclic ester Acetonitrile
    Figure US20040147543A1-20040729-C00162
    114 4-(Dimethylamino)phenyl boronic acid Acetonitrile
    Figure US20040147543A1-20040729-C00163
    115 5-(tert-Butyldimethylsilanyloxymethyl) pyridine-3-boronic acid Not used
    Figure US20040147543A1-20040729-C00164
    116 Pyridine-4-boronic acid pinacol ester Acetonitrile
    Figure US20040147543A1-20040729-C00165
  • Example 106 2-Ethoxymethyl-1-(2-methylpropyl)-7-(3-propoxyphenyl)-1H-imidazo[4,5-c]quinolin-4-amine
  • The product was obtained as an off-white powder, mp 140.0-141.0° C. [0590]
  • Anal. Calcd for C[0591] 26H32N4O2: C, 72.19; H, 7.46; N, 12.95. Found: C, 71.88; H, 7.36; N, 12.72.
  • Example 107 2-Ethoxymethyl-1-(2-methylpropyl)-7-(4-propoxyphenyl)-1H-imidazo[4,5-c]quinolin-4-amine
  • The product was obtained as a white solid, mp 209.0-210.0° C. [0592]
  • Anal. Calcd for C[0593] 26H32N4O2: C, 72.19; H, 7.46; N, 12.95. Found: C, 71.93; H, 7.41; N, 12.76.
  • Example 108 2-Ethoxymethyl-1-(2-methylpropyl)-7-phenyl-1H-imidazo[4,5-c]quinolin-4-amine
  • The product was obtained as a white solid, mp 176.5-178.0° C. [0594]
  • Anal. Calcd for C[0595] 23H26N4O: C, 73.77; H, 7.00; N, 14.96. Found: C, 73.65; H, 6.90; N, 14.80.
  • Example 109 2-Ethoxymethyl-1-(2-methylpropyl)-7-(2-propoxyphenyl)-1H-imidazo[4,5-c]quinolin-4-amine
  • The product was obtained as light-yellow needles, mp 168.0-169.0° C. [0596]
  • Anal. Calcd for C[0597] 26H32N4O2: C, 72.19; H, 7.46; N, 12.95. Found: C, 71.96; H, 7.40; N, 13.13.
  • Example 110 4-(4-Amino-2-ethoxymethyl-1-(2-methylpropyl)- I H-imidazo[4,5-c]quinolin-7-yl)benzonitrile
  • The product was obtained as an off-white solid, mp 211.0-212.0° C. [0598]
  • Anal. Calcd for C[0599] 24H25N5O: C, 72.16; H, 6.31; N, 17.53. Found: C, 71.87; H, 6.22; N, 17.40.
  • Example 111 3-(4-Amino-2-ethoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c] quinolin-7-yl)benzonitrile
  • The product was obtained as light-brown crystals, mp 210.0-211.0° C. [0600]
  • Anal. Calcd for C[0601] 24H25N5O: C, 72.16; H, 6.31; N, 17.53. Found: C, 71.88; H, 6.06; N, 17.63.
  • Example 112 2-Ethoxymethyl-1-(2-methylpropyl)-7- {(E)-2-[(4-trifluoromethyl)phenyl]vinyl}-1H-imidazo[4,5-c]quinolin-4-amine
  • The product was obtained as light-yellow needles, mp 193.0-194.0° C. [0602]
  • Anal. Calcd for C[0603] 26H27F3N4O: C, 66.65; H, 5.81; N, 11.96. Found: C, 66.51; H, 5.76; N, 11.96.
  • Example 113 2-Ethoxymethyl-1-(2-methylpropyl)-7-(pyridin-3-yl)- I H-imidazo[4,5-c]quinolin-4-amine
  • Following recrystallization from acetonitrile, the crystals were purified by flash column chromatography on silica gel. The polar component of the eluent was a mixture of chloroform:methanol:ammonium hydroxide 80:18:2 (CMA). The chromatographic separation was carried out eluting sequentially with 95:5, 90:10, 85:15, 80:20, and 75:25 chloroform:CMA. The fractions containing the product were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure until a precipitate began to form. Hexanes were added, and the resulting solid was isolated by filtration to provide 2-ethoxymethyl-1-(2-methylpropyl)-7-pyridin-3-yl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 179.5-181.5° C. [0604]
  • Anal. Calcd for C[0605] 22H25N5O: C, 70.38; H, 6.71; N, 18.65. Found: C, 70.07; H, 6.87; N, 18.57.
  • Example 114 7-(4-Dimethylaminophenyl)-2-ethoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine
  • The product was obtained as a yellow solid, mp 214.5-215.5° C. [0606]
  • Anal. Calcd for C[0607] 25H31N5O: C, 71.91; H, 7.48; N, 16.77. Found: C, 71.66; H, 7.40; N, 16.71.
  • Example 115 {5-[4-Amino-2-ethoxyrnethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]pyridin-3-yl}methanol
  • Part A [0608]
  • 3-Bromo-5-(tert-butyldimethylsilanyloxymethyl)pyridine was prepared according to the published procedure (Zhang, N. et al, [0609] J. Med. Chem., 45, 2832-2840 (2002)). Under a nitrogen atmosphere, a solution of 3-bromo-5-(tert-butyldimethylsilanyloxymethyl)pyridine (28.70 g, 94.94 mmol) and triisopropyl borate (26.3 mL, 114 mmol) in dry THF was cooled to −70° C. n-Butyllithium (45.6 mL, 114 mmol) was added dropwise over a period of 1.5 hours. The reaction was stirred for an additional 30 minutes and then allowed to warm to −20° C. Dilute aqueous ammonium chloride was added, and the mixture was allowed to warm to ambient temperature. The aqueous layer was separated and extracted with diethyl ether. The combined organic fractions were concentrated under reduced pressure, and methanol was added to the resulting oil. A solid formed, which was stirred with water for two days, isolated by filtration, and dried under reduced pressure to provide 18.19 g of 5-(tert-butyldimethylsilanyloxymethyl)pyridine-3-boronic acid as a white solid.
  • Part B [0610]
  • The coupling reaction was heated at reflux for four days, and the product was purified on a Biotage HORIZON High-Performance Flash Chromatography instrument (HPFC) (eluting with chloroform:CMA in a gradient from 100:0 to 55:45.) The fractions containing the product were combined and concentrated under reduced pressure until a precipitate began to form. Hexanes were added, and the resulting solid was isolated by filtration and dried overnight in an oven at 70° C. to provide [5-(4-amino-2-ethoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl)pyridin-3-yl]methanol as an off-white powder, mp 211.0-212.0° C. [0611]
  • Anal. Calcd for C[0612] 23H27N5O2: C, 68.13; H, 6.71; N, 17.27. Found: C, 68.04; H, 7.07; N, 17.21.
  • Example 116 2-Ethoxymethyl-1-(2-methylpropyl)-(7-pyridin-4-yl)-1H-imidazo [4,5-c]quinolin-4-amine
  • The reaction was heated at reflux for 48 hours, and the reaction mixture was partitioned between aqueous sodium chloride and dichloromethane. The aqueous layer was extracted twice with dichloromethane, and the combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 95:5 to 80:20) followed by recrystallization from acetonitrile to provide 2-ethoxymethyl-1-(2-methylpropyl)-(7-pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 211-213° C. [0613]
  • Anal. Calcd for C[0614] 22H25N5O: C, 70.38; H, 6.71; N, 18.65. Found: C, 70.33; H, 6.76; N, 18.69.
  • Example 117 2-Ethoxymethyl-1-(2-methylpropyl)-7-{2-[(trifluoromethyl)phenyl]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine
  • [0615]
    Figure US20040147543A1-20040729-C00166
  • A solution of 2-ethoxymethyl-1-(2-methylpropyl)-7-{(E)-2-[(4-trifluoromethyl)phenyl]vinyl}-1H-imidazo[4,5-c]quinolin-4-amine (0.47 g, 1.0 mmol) in ethyl acetate (200 mL) was added to a Parr vessel charged with 10% palladium on carbon (0.30 g). The reaction was placed under hydrogen pressure (50 psi, 3.4×10[0616] 5 Pa) for seven days. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to provide 0.22 g of 2-ethoxymethyl-1-(2-methylpropyl)-7-{2-[(4-trifluoromethyl)phenyl]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, mp 175.5-178° C.
  • Anal. Calcd for C[0617] 26H29F3N4O: C, 66.37; H, 6.21; N, 11.91. Found: C, 66.09; H, 6.39; N, 11.53.
  • Examples 118-122
  • For Examples 118-121, triphenylphosphine (31 mg, 0.12 mmol) and palladium (II) acetate (9 mg, 0.04 mmol) were added to a mixture of 8-bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.28 g, 4.00 mmol), the boronic acid from the table below (6.00 mmol, 1.5 equivalents), n-propanol (7 mL), aqueous sodium carbonate (5.0 mL of 2 M), and water (1.4 mL). The reaction was purged with nitrogen and heated at reflux under a nitrogen atmosphere for one to two hours. Upon cooling to ambient temperature, a solid formed and was isolated by filtration and washed with water. The crude product was recrystallized from methanol and dried overnight at 1.33 Pa and 98° C. to provide the products listed below the table. [0618]
  • For Example 122, 8-bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine and the boronic acid from the table below were coupled according to the general procedure described in Part J of Example 1. The reaction was heated at reflux overnight. The crude product was recrystallized from methanol. [0619]
  • Examples 118-122
  • [0620]
    Figure US20040147543A1-20040729-C00167
    Example Boronic acid or ester R3
    118 4-Ethylphenylboronic acid
    Figure US20040147543A1-20040729-C00168
    119 3,4-Dimethylphenylboronic acid
    Figure US20040147543A1-20040729-C00169
    120 3-Acetylphenylboronic acid
    Figure US20040147543A1-20040729-C00170
    121 Thianaphthene-3-boronic acid
    Figure US20040147543A1-20040729-C00171
    122 trans-2-Phenylvinylboronic acid
    Figure US20040147543A1-20040729-C00172
  • Example 118 8-(4-Ethylphenyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine
  • The product was obtained as pale yellow needles, mp 238-240° C. [0621]
  • Anal. Calcd for C[0622] 22H24N4: C, 76.71; H, 7.02; N, 16.26. Found: C, 76.67; H, 7.00N; 16.31.
  • Example 119 8-(3,4-Dimethylphenyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine
  • The product was obtained as pale yellow needles, mp 204-205° C. [0623]
  • Anal. Calcd for C[0624] 22H24N4: C, 76.71; H, 7.02; N, 16.26. Found: C, 76.33; H, 7.28; N, 16.21.
  • Example 120 1-{3-[4-Amino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-8-yl]phenyl}ethanone
  • The product was obtained as a white solid, mp 217-218° C. [0625]
  • Anal. Calcd for C[0626] 22H22N4O: C, 73.72; H, 6.19; N, 15.63. Found: C, 73.87; H, 6.24; N, 15.75.
  • Example 121 8-Benzo[b]thiophen-3-yl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine
  • The product was obtained as pale yellow needles, mp 247-248° C. [0627]
  • Anal. Calcd for C[0628] 22H20N4S.0.14H2O: C, 70.46; H, 5.45; N, 14.94. Found: C, 70.28; H, 5.26; N, 14.91.
  • Example 122 1-(2-Methylpropyl)-8-styryl-1H-imidazo[4,5-c]quinolin-4-amine
  • The product was obtained as pale yellow crystals, mp 228-230° C. [0629]
  • Anal. Calcd for C[0630] 22H22N4.1.5H20: C, 71.52; H, 6.82; N, 15.16. Found: C, 71.34; H, 6.63; N, 15.20.
  • Example 123 1-(2-Methylpropyl)-8-phenethyl-1H-imidazo[4,5-c]quinolin-4-amine
  • [0631]
    Figure US20040147543A1-20040729-C00173
  • A solution of 1-(2-methylpropyl)-8-styryl-1H-imidazo[4,5-c]quinolin-4-amine (1.37 g, 4.00 mmol) in ethanol (40 mL) was added to a Parr vessel charged with 10% palladium on carbon (137 mg). The reaction was placed under hydrogen pressure (40 psi, 2.8×10[0632] 5 Pa) for six days. The reaction mixture was filtered through a layer of CELITE filter aid, and the filter cake was washed with ethanol. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from methanol to provide 0.300 g of 1-(2-methylpropyl)-8-phenethyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 175-178° C.
  • Anal. Calcd for C[0633] 22H24N4.0.75H20: C, 73.82; H, 7.18; N, 15.65. Found: C, 73.45; H, 7.32; N, 15.33.
  • Example 124 2-Methyl-1-(3-methanesulfonylpropyl)-7-phenyl-1H-imidazo[4,5-c]quinolin-4-amine
  • [0634]
    Figure US20040147543A1-20040729-C00174
  • Part A [0635]
  • N[0636] 4-(3-Methylsulfanylpropyl)-7-phenylquinoline-3,4-diamine and trimethyl orthoacetate were reacted according to the general method described in Part H of Example 10. The crude product was purified by column chromatography on silica gel (eluting with 95:5 dichloromethane:methanol) to provide 2-methyl-1-(3-methanesulfanylpropyl)-7-phenyl-1H-imidazo[4,5-c]quinolin-4-amine as a light brown solid.
  • Part B [0637]
  • The method described in Part I of Example 10 was followed. The crude product was recrystallized from acetonitrile (67 mL/g) and then from methanol (106 mL/g). The crystals were purified by column chromatography on silica gel (eluting with 90:10 dichloromethane:methanol), and the resulting solid was recrystallized from acetonitrile (220 mL/g) and dried for 17 hours under vacuum at 85° C. to provide 2-methyl-1-(3-methanesulfonylpropyl)-7-phenyl-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, mp mp 203-205° C. [0638]
  • Anal. Calcd for C[0639] 21H22N4O2S: C, 63.94; H, 5.62: N, 14.20. Found: C, 63.81; H, 5.47; N, 14.14.
  • Examples 125-135
  • Part A [0640]
  • Triethylamine (17.35 mL, 124 mmol) was added to a solution of 7-bromo-4-chloro-3-nitroquinoline (29.84 g, 104 mmol) in dichloromethane (253 mL), and the reaction was cooled to 0° C. 1-Amino-2-methylpropan-2-ol (10.17 g, 114 mmol) was added dropwise, and then the reaction was allowed to warm to ambient temperature and stirred overnight. A precipitate formed and was isolated by filtration and washed with water. The crude solid was recrystallized from a mixture of isopropanol and acetonitrile to provide 27.78 g of 1-(7-bromo-3-nitroquinolin-4-ylamino)-2-methylpropan-2-ol as a solid. [0641]
  • Part B [0642]
  • A solution of 1-(7-bromo-3-nitroquinolin-4-ylamino)-2-methylpropan-2-ol (27.78 g, 81.66 mmol) in acetonitrile (1.2 L) was added to a Parr vessel charged with 5% platinum on carbon (0.84 g), and the reaction was placed under hydrogen pressure (50 psi, 3.4×10[0643] 5 Pa) for two days. The reaction mixture was filtered through a layer of CELITE filter aid, and the filter cake was washed with ethanol (1 L). The filtrate was concentrated under reduced pressure to provide 21.70 g of 1-(3-amino-7-bromoquinolin-4-ylamino)-2-methylpropan-2-ol as a yellow oil.
  • Part C [0644]
  • A solution of 1-(3-amino-7-bromoquinolin-4-ylamino)-2-methylpropan-2-ol (158.19 g, 0.510 mol) in dichloromethane (1.2 L) was cooled to 0° C. Ethoxyacetyl chloride (62.50 g, 0.510 mol) was added dropwise, and then the reaction was allowed to warm to ambient temperature and stirred overnight. A precipitate formed and was isolated by filtration to provide N-[7-bromo-4-(2-hydroxy-2-methylpropylamino)quinolin-3-yl]-2-ethoxyacetamide as a solid. [0645]
  • Part D [0646]
  • A solution of sodium hydroxide (25 g, 0.625 mol) in water (205 mL) was added to a solution of N-[7-bromo-4-(2-hydroxy-2-methylpropylamino)quinolin-3-yl]-2-ethoxyacetamide (170.88 g, 0.431 mol) in ethanol (700 mL), and the reaction was heated at reflux under a nitrogen atmosphere for two hours. Upon cooling the reaction, a precipitate formed and was isolated by filtration. The solid was purified by flash column chromatography on silica gel (eluting sequentially with chloroform, 99:1 chloroform:methanol, and 97:3 chloroform:methanol) to provide 80.31 g of 1-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as a tan solid. [0647]
  • Part E [0648]
  • 3-Chloroperoxybenzoic acid (73.27 g of 50% pure material, 0.212 mol) was added in four portions over a period of 30 minutes to a solution of 1-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c] quinolin-1-yl)-2-methylpropan-2-ol (80.31 g, 0.212 mol) in dichloromethane (950 mL), and the reaction was stirred overnight at ambient temperature. The reaction mixture was washed twice with aqueous sodium carbonate (2 M) and then diluted with additional dichloromethane (1.5 L total volume). The solution was cooled to 0° C., and concentrated ammonium hydroxide (83 mL) was added. p-Toluenesulfonyl chloride (48.56 g, 0.254 mol) was then added over a period of 20 minutes, and the reaction was allowed to warm to ambient temperature and stirred overnight. A precipitate formed and was isolated by filtration and washed sequentially with 2 M aqueous sodium carbonate and water. The crude product was recrystallized from 2:1 isopropanol:acetonitrile and collected in two crops to provide 58.4 g of 1-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as a solid. [0649]
  • Part F [0650]
  • 1-(4-Amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol and the boronic acid or boronic acid ester from the table below were coupled according to the general procedure described in Part J of Example 1. The reaction was heated at reflux for between 1.5 and 27 hours. The reaction mixture was partitioned between brine and chloroform. The aqueous layer was extracted twice with chloroform, and the combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The purification and characterization of each compound is given below the table. [0651]
  • Examples 125-135
  • [0652]
    Figure US20040147543A1-20040729-C00175
    Example Boronic acid or ester R3
    125 Thiophene-3-boronic acid
    Figure US20040147543A1-20040729-C00176
    126 Pyridine-3-boronic acid 1,3-propanediol cyclic ester
    Figure US20040147543A1-20040729-C00177
    127 Pyridine-4-boronic acid pinacol ester
    Figure US20040147543A1-20040729-C00178
    128 1H-Pyrazole-4-boronic acid pinacol ester
    Figure US20040147543A1-20040729-C00179
    129 3-(Pyrrolidine-1-carbonyl)phenylboronic acid
    Figure US20040147543A1-20040729-C00180
    130 3-(Morpholine-4- carbonyl)phenylboronic acid
    Figure US20040147543A1-20040729-C00181
    131 Phenylboronic acid
    Figure US20040147543A1-20040729-C00182
    132 4-(N,O- Dimethylhydroxylaminocarbonyl)phenyl boronic acid
    Figure US20040147543A1-20040729-C00183
    133 5-(tert-Butyldimethylsilanyloxymethyl) pyridine-3-boronic acid
    Figure US20040147543A1-20040729-C00184
    134 5-Ethoxymethylpyridin-3-ylboronic acid
    Figure US20040147543A1-20040729-C00185
    135 3-Carboxyphenylboronic acid
    Figure US20040147543A1-20040729-C00186
  • Example 125 1-[4-Amino-2-ethoxymethyl-7-(thiophen-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol
  • The crude product was recrystallized from 2-butanone and then purified by flash column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 90:10 to 65:35). The resulting solid was recrystallized from acetonitrile to provide 1-[4-amino-2-ethoxymethyl-7-(thiophen-3-yl)-1H-imidazol[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as white crystals, mp 204-205° C. [0653]
  • Anal Calcd for C[0654] 21H24N4O2S: C, 63.61; H, 6.10; N, 14.13. Found: C, 63.71; H, 6.23N; 4.31.
  • Example 126 1-[4-Amino-2-ethoxymethyl-7-(pyridin-3-yl)- H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol
  • The crude product was purified three times by HPFC (eluting with chloroform:CMA in a gradient from 90:10 to 70:30). The resulting solid was recrystallized from acetonitrile and dried overnight at 1.33 Pa and 98° C. to provide 1-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as a white solid, mp 197-199° C. [0655]
  • Anal. Calcd for C[0656] 22H25N5O2.0.28H2O: C, 66.63; H, 6.50; N, 17.66. Found: C, 66.63; H, 6.55; N, 17.88.
  • Example 127 1-[4-Amino-2-ethoxymethyl-7-(pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol
  • The crude product was purified twice by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 55:45). The fractions containing the pure product were concentrated under reduced pressure until a precipitate formed. Hexanes were added, and the resulting solid was isolated by filtration and dried overnight under vacuum to provide 1-[4-amino-2-ethoxymethyl-7-(pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as a pale yellow solid, mp 220-221° C. [0657]
  • Anal. Calcd for C[0658] 22H25N5O2.0.39H2O: C, 66.31; H, 6.52; N, 17.57. Found: C, 65.95; H, 6.32; N, 17.44.
  • Example 128 1-[4-Amino-2-ethoxymethyl-7-(1H-pyrazol-4-yl)-1H-imidazo[4,5-c]quinolin 1-yl]-2-methylpropan-2-ol
  • The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 40:60) followed by recrystallization from methanol to provide 1-[4-amino-2-ethoxymethyl-7-(1H-pyrazol-4-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as white, granular crystals, mp >250° C. [0659]
  • Anal. Calcd for C[0660] 20H24N6O2: C, 63.14; H, 6.36; N, 22.09. Found: C, 62.89; H, 6.35; N, 21.94.
  • Example 129 {3-[4-Amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]phenyl}pyrrolidin-1-ylmethanone
  • The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 65:35) followed by recrystallizations from isopropanol and acetonitrile to provide {3-[4-amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]phenyl}pyrrolidin-1-ylmethanone as a white powder, mp 216.5-217.5° C. [0661]
  • Anal. Calcd for C[0662] 28H33N5O3: C, 68.97; H, 6.82; N, 14.36. Found: C, 68.67; H, 7.01; N, 14.42.
  • Example 130 {3-[4-Amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]phenyl}morpholin-4-ylmethanone
  • The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 70:30) followed by recrystallizations from isopropanol, dichloromethane:hexanes, and isopropanol. The crystals were dried under vacuum with heating to provide {3-[4-amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]phenyl}morpholin-4-ylmethanone as a white powder, mp 152.0-154.0° C. [0663]
  • Anal. Calcd for C[0664] 28H33N5O4.0.5H2O: C, 65.61; H, 6.69; N, 13.66. Found: C, 65.67; H, 7.09; N, 13.72.
  • Example 131 1-(4-Amino-2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol
  • The crude product was recrystallized from methanol:water and then 30 purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 70:30) to provide 1-(4-amino-2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as a white solid, mp 211-212° C. [0665]
  • [0666] 1H NMR (500 mHz, DMSO-d6) δ 8.34 (d, J=8.5 Hz, 1H), 7.83 (d, J=2 Hz, 1H), 7.76-7.73 (m, 2H), 7.52-7.46 (m, 3H), 7.38-7.35 (m, 1H), 6.58 (br s, 2H), 4.88 (s, 3H), 4.68 (br s, 2H), 3.52 (q, J=7 Hz, 2H), 1.19 (br s, 6H), 1.13 (t, J=7 Hz, 3H);
  • HRMS (ESI) m/z 391.2124 (391.2134 calcd for C[0667] 23H26N4O2, (M+H).
  • Example 132 4-[4-Amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]-N-methoxy-N-methylbenzamide
  • The crude product was purified three times by HPFC (eluting with chloroform:CMA in gradients from 100:0 to 70:30). The fractions containing the pure product were concentrated under reduced pressure until a precipitate formed. Hexanes were added, and the resulting solid was isolated by filtration and dried overnight in a vacuum oven at 80° C. and then heated to melting under vacuum to provide 4-[4-amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]-N-methoxy-N-methylbenzamide as a light green solid. [0668]
  • [0669] 13C NMR (75 MHz, DMSO-d6) δ 168.7, 152.3, 151.0, 145.5, 141.9, 137.0, 133.9, 133.0, 128.5, 126.2, 123.7, 122.2, 119.1, 114.8, 70.6, 65.2, 64.8, 60.7, 54.8, 33.2, 27.6, 14.9;
  • HRMS (El) m/z 478.2446 (478.2454 calcd for C[0670] 26H31N5O4).
  • Example 133 1-[4-Amino-2-ethoxymethyl-7-(5-hydroxymethylpyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol
  • The reaction was heated at reflux for three hours and then allowed to cool and stand at ambient temperature for several days. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 65:35). The solid (3.73 g) was dissolved in tetrahydrofuran (THF) (5 mL), water (5 mL), and acetic acid (15 mL). The solution was allowed to stand at room temperature for three days, and then the solvents were removed under reduced pressure. The residue was partitioned between chloroform and 2 M aqueous sodium carbonate:brine, and the aqueous layer was extracted with chloroform (7×). The combined organic fractions were concentrated under reduced pressure. The residue was then purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 35:65) followed by recrystallization from acetonitrile to provide 1-[4-amino-2-ethoxymethyl-7-(5-hydroxymethylpyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as a white powder, mp 188-190° C. [0671]
  • Anal. Calcd for C[0672] 23H27N5O3: C, 65.54; H, 6.46; N, 16.62. Found: C, 65.22; H, 6.66; N, 16.56.
  • Example 134 1-[4-Amino-2-ethoxymethyl-7-(5-ethoxymethylpyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol
  • Part A [0673]
  • (5-Bromopyridin-3-yl)methanol was prepared according to the published procedure (Zhang, N. et al, [0674] J. Med. Chem., 45, 2832-2840 (2002)). A solution of (5-bromopyridin-3-yl)methanol (7.39 g, 39.3 mmol) in THF was cooled to 0° C. Sodium bis(trimethylsilyl)amide (39.3 mL of a 1.0 M solution in THF) was added, and the reaction was stirred for 20 minutes. lodoethane (3.46 mL, 43.2 mmol) and DMF were added, and the reaction was allowed to warm to ambient temperature and stirred overnight. Brine was added, and the aqueous layer was extracted twice with hexanes. The combined organic fractions were concentrated under reduced pressure, and the residue was purified by HPFC (eluting with hexanes:ethyl acetate in a gradient from 100:0 to 70:30) to provide 5.11 g of 3-bromo-5-ethoxymethylpyridine as a colorless oil.
  • Part B [0675]
  • The method described in Part A of Example 115 was used to convert 3-bromo-5-ethoxymethylpyridine (5.11 g, 23.6 mmol) to 5-ethoxymethylpyridin-3-ylboronic acid, which was obtained as a white solid. [0676]
  • Part C [0677]
  • The crude product from the coupling reaction was recrystallized from dichloromethane:hexanes and then purified twice by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 70:30). The resulting solid was recrystallized from dichloromethane:hexanes to provide 1-[4-amino-2-ethoxymethyl-7-(5-ethoxymethylpyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as a white powder, mp 156.0-156.5° C. [0678]
  • Anal. Calcd for C[0679] 25H31N5O3: C, 66.79; H, 6.95; N, 15.58. Found: C, 66.46; H, 6.98; N, 15.51.
  • Example 135 3-[4-Amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]benzoic acid
  • The crude product was isolated as a solid from the reaction mixture, recrystallized from dimethyl sulfoxide, stirred with methanol:water, and isolated by filtration to provide 3-[4-amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]benzoic acid as a white powder, mp >250° C. [0680]
  • HRMS (ESI) m/z 435.2016 (435.2032 calcd for C[0681] 24H26N4O4, (M+H).
  • Examples 136-141
  • Part A [0682]
  • The method described in Part A of Example 9 was used to react 1-(3-amino-7-bromoquinolin-4-ylamino)-2-methylpropan-2-ol (29.0 g, 93.5 mmol) with 3-methoxypropionyl chloride (11.5 g, 93.5 mmol). The crude product was recrystallized from 2:1 ethyl acetate:hexane and then purified by flash column chromatography on silica gel (eluting sequentially with 60:40 acetone:toluene and acetone). The resulting solid was recystallized from 3:1 ethyl acetate hexane to provide 13.3 g of 1-[7-bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as translucent crystals. [0683]
  • Part B [0684]
  • 1-[7-Bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol was oxidized and then aminated according to the methods described in Parts H and I of Example 1. After recrystallization from ethanol, 1-[4-amino-7-bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol was obtained as a pale orange solid. [0685]
  • Part C [0686]
  • 1-[4-Amino-7-bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol and the boronic acid or boronic acid ester from the table below were coupled according to the general procedure described in Part J of Example 1. The reaction was heated at reflux for between three hours and overnight. For Example 136, a solid formed upon cooling to room temperature aqnd was isolated by filtration and washed with hexanes. For Examples 137-141, the reaction mixture was partitioned between brine and chloroform. The aqueous layer was extracted twice with chloroform, and the combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The purification and characterization of each compound is given below the table. [0687]
  • Examples 136-141
  • [0688]
    Figure US20040147543A1-20040729-C00187
    Example Boronic acid or ester R3
    136 Phenylboronic acid
    Figure US20040147543A1-20040729-C00188
    137 Thiophene-3-boronic acid
    Figure US20040147543A1-20040729-C00189
    138 Pyridine-3-boronic acid 1,3-propanediol cyclic ester
    Figure US20040147543A1-20040729-C00190
    139 3-(Methylsulfonylamino)phenylboronic acid
    Figure US20040147543A1-20040729-C00191
    140 3-(Hydroxymethyl)phenylboronic acid
    Figure US20040147543A1-20040729-C00192
    141 5-(tert-Butyldimethylsilanyloxymethyl pyridine-3-boronic acid
    Figure US20040147543A1-20040729-C00193
  • Example 136 1-[4-Amino-2-(2-methoxyethyl)-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol
  • The crude product was recrystallized twice from isopropanol and then from dichloromethane:hexanes and dried overnight under vacuum to provide 1-[4-amino-2-(2-methoxyethyl)-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as a white solid, mp 226-227° C. [0689]
  • Anal. Calcd for C[0690] 23H26N4O2: C, 70.75; H, 6.71; N, 14.35. Found: C, 70.49; H, 6.56; N, 14.28.
  • Example 137 1-[4-Amino-2-(2-methoxyethyl)-7-(thiophen-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol
  • The crude product purified by flash column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 85:15 to 70:30). The resulting solid was recrystallized from ethanol to provide 1-[4-amino-2-(2-methoxyethyl)-7-(thiophen-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as white crystals, mp 233-234° C. [0691]
  • Anal. Calcd for C[0692] 21H24N4O2S: C, 63.61; H, 6.10; N, 14.13. Found: C, 63.45; H, 6.21; N, 14.07.
  • Example 138 1-[4-Amino-2-(2-methoxyethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol
  • The crude product was purified by flash column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 90:10 to 70:30). The resulting solid was recrystallized from methanol to provide 1-[4-amino-2-(2-methoxyethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as white needles, mp 158-160° C. [0693]
  • Anal. Calcd for C[0694] 22H25N5O2.1.10H2O: C, 64.26; H, 6.67; N, 17.03. Found: C, 64.12; H, 7.02; N, 17.27.
  • Example 139 N-{3-[4-Amino-1-(2-hydroxy-2-methylpropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-7-yl]phenyl}methanesulfamide
  • The crude product was purified by flash column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 90:10 to 80:20) to provide N-{3-[4-amino-1-(2-hydroxy-2-methylpropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-7-yl]phenyl}methanesulfamide as a white powder, mp 156-158° C. [0695]
  • Anal. Calcd for C[0696] 24H29N5O4S.3.0H2O: C, 53.62; H, 6.56; N, 13.03. Found: C, 53.50; H, 6.49; N, 12.95.
  • Example 140 1-[4-Amino-7-(3-hydroxymethylphenyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol
  • The crude product was purified by flash column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 90:10 to 80:20) to provide 1-[4-amino-7-(3-hydroxymethylphenyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as a white powder, mp 212-213° C. [0697]
  • Anal. Calcd for C[0698] 24H28N4O3.0.17H2O: C, 68.06; H, 6.74; N, 13.22. Found: C, 67.73; H, 6.63; N, 13.04.
  • Example 141 1-[4-Amino-7-(5-hydroxymethylpyridin-3-yl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol
  • The crude product was purified by flash column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 90:10 to 80:20) to provide 1-[4-amino-7-(5-hydroxymethylpyridin-3-yl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as a yellow solid, mp 210-211° C. [0699]
  • Anal. Calcd for C[0700] 23H27N5O3.1.0H2O: C, 62.85; H, 6.65; N, 15.93. Found: C, 62.47; H, 6.33; N, 15.83.
  • Examples 142-144
  • Part A [0701]
  • Triethyl orthopropionate (12.9 g, 73.2 mmol) and pyridine hydrochloride (220 mg) were added to a solution of 1-(3-amino-7-bromoquinolin-4-ylamino)-2-methylpropan-2-ol (22.1 g, 70.6 mmol) in anhydrous toluene (300 mL), and the reaction was heated at reflux for three hours. The reaction was allowed to cool to ambient temperature and stand overnight; a precipitate formed. The precipitate was isolated by filtration, washed with toluene, and air-dried to provide 18.42 g of 1-(7-bromo-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as beige crystals. [0702]
  • Part B [0703]
  • 1-(7-Bromo-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol was oxidized and then aminated according to the methods described in Parts H and I of Example 1. The product from amination was isolated by filtration from the reaction mixture and stirred with 2 M aqueous sodium carbonate and chloroform for ten minutes. The resulting solid was isolated by filtration and washed with water to provide 1-(4-amino-7-bromo-2-methoxyethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as a white solid, which was used without further purification. [0704]
  • Part C [0705]
  • 1-(4-Amino-7-bromo-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol and the boronic acid or boronic acid ester from the table below were coupled according to the general procedure described in Part J of Example 1. The reaction was heated at reflux between 12 and 54 hours. The work-up procedure described in Part F of Examples 125-131 was followed, and the purification and characterization of each compound is described below the table. [0706]
  • Examples 142-144
  • [0707]
    Figure US20040147543A1-20040729-C00194
    Example Boronic acid or ester R3
    142 Pyridine-3-boronic acid 1,3- propanediol cyclic ester
    Figure US20040147543A1-20040729-C00195
    143 Pyridine-4-boronic acid pinacol ester
    Figure US20040147543A1-20040729-C00196
    144 5-(tert- Butyldimethylsilanyloxymethyl) pyridine-3-boronic acid
    Figure US20040147543A1-20040729-C00197
  • Example 142 1-[4-Amino-2-ethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol
  • The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 55:45). The resulting solid was dissolved in chloroform and precipitated with hexane, recrystallized twice from acetonitrile, and finally recystallized from 3:1 acetonitrile:methanol and dried at 1.33 Pa and 80° C. to provide 1-[4-amino-2-ethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as white needles, mp 245-247° C. [0708]
  • Anal. Calcd for C[0709] 21H23N5O: C, 69.78; H, 6.41; N, 19.38. Found: C, 69.60; H, 6.53; N, 19.58.
  • Example 143 1-[4-Amino-2-ethyl-7-(pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol
  • The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 65:35) The resulting solid was recrystallized from acetonitrile:methanol and air-dried to provide 1-[4-amino-2-ethyl-7-(pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as a white solid, mp >250° C. [0710]
  • Anal. Calcd for C[0711] 21H23N5O: C, 69.78; H, 6.41; N, 19.38. Found: C, 69.68; H, 6.54; N, 19.43.
  • Example 144 1-[4-Amino-2-ethyl-7-(5-hydroxymethylpyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol
  • The crude product was purified by HPFC, and the resulting solid was dissolved in THF (5 mL), water (5 mL), and acetic acid (15 mL). The solution was allowed to stand at room temperature for three days, and 5 M aqueous sodium hydroxide and 2 M aqueous sodium carbonate were added to adjust to pH 11. A solid was present and was isolated by filtration and purified by HPFC™ (eluting with chloroform:CMA in a gradient from 100:0 to 35:65). The resulting solid was recrystallized from 3:1 methanol:acetonitrile and dried overnight at 1.33 Pa and 80° C. to provide 1-[4-amino-2-ethyl-7-(5-hydroxymethylpyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as white crystals, mp >250° C. [0712]
  • Anal. Calcd for C[0713] 22H25N5O2: C, 67.50; H, 6.44; N, 17.89. Found: C, 67.28; H, 6.71; N, 18.06.
  • Example 145 2-(2-Methoxyethyl)-1-(2-methylpropyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine
  • [0714]
    Figure US20040147543A1-20040729-C00198
  • 7-Bromo-2-(2-methoxyethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine was prepared according to the procedures described in Parts A and B of Example 9 using methoxypropanoyl chloride instead of ethoxyacetyl chloride. 7-Bromo-2-(2-methoxyethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine was coupled with pyridine-3-boronic acid 1,3-propanediol cyclic ester according to the method described in Examples 118-121. The reaction was heated at reflux overnight, and the work-up procedure described in Part F of Examples 125-131 was followed. The crude product was purified by flash column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 90:10 to 76:24) followed by recrystallization from methanol. The crystals were dried at 1.33 Pa and 98° C. to provide 2-(2-methoxyethyl)-1-(2-methylpropyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as white needles, mp 207-208° C. [0715]
  • Anal. Calcd for C[0716] 22H25N5O: C, 70.38; H, 6.71; N, 18.65. Found: C, 70.31; H, 6.76; N, 18.76.
  • Example 146 {5-[4-Amino-2-(2-methoxyethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]pyridin-3-yl }methanol
  • [0717]
    Figure US20040147543A1-20040729-C00199
  • 7-Bromo-2-(2-methoxyethyl)-1-(2-methylpropyl)-1H-imidazo[4,5- c]quinolin-4-amine was coupled with 5-(tert-butyldimethylsilanyloxymethyl)pyridine-3-boronic acid according to the method described in Examples 118-121. The reaction was heated at reflux for 2.25 hours, and the work-up procedure described in Part F of Examples 125-131 was followed. The crude product was purified and deprotected according to the procedure described in Example 144. The resulting solid was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 55:45) followed by recrystallization from acetonitrile to provide {5-[4-amino-2-(2-methoxyethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]pyridin-3-yl}methanol as white needles, mp 202-204° C. [0718]
  • Anal. Calcd for C[0719] 23H27N5O2: C, 68.13; H, 6.71; N, 17.27. Found: C, 67.89; H, 6.62; N, 17.26.
  • Examples 147-150
  • Part A [0720]
  • 6-Bromo-4-chloro-3-nitroquinoline, prepared from 4-bromoaniline according to the methods described in Parts A-D of Example 1, was treated according to the methods described in Parts A and B of Examples 125-135 to provide 1-(3-amino-6-bromoquinolin-4-ylamino)-2-methylpropan-2-ol. [0721]
  • Part B [0722]
  • 1-(3-Amino-6-bromoquinolin-4-ylamino)-2-methylpropan-2-ol was treated according to the method described in Parts A and B of Example 9 to provide 1-(4-amino-8-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol. [0723]
  • Part C [0724]
  • 1-(4-Amino-8-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol and the boronic acid or boronic acid ester from the table below were coupled according to the general procedure described in Part J of Example 1. The reaction was stirred overnight. The crude product was purified by flash column chromatography on silica gel (eluting sequentially with 95:5 and 90:10 dichloromethane:methanol) followed by recrystallization from methanol to provide the products shown in the table below. [0725]
  • For Example 150, the product from the coupling reaction (1.5 g, 2.8 mmol) was dissolved in THF (25 mL). Tetrabutylammonium fluoride (3.64 mL of a 1.0 M solution in THF) was added, and the reaction was stirred for one hour at ambient temperature. Saturated ammonium chloride (20 mL) was added, and the aqueous layer was separated and extracted with dichloromethane (3×50 mL). The combined organic fractions were dried over sodium sulfate and filtered. A precipitate formed in the filtrate and was isolated by filtration. The solid was washed with dichloromethane, stirred with methanol, isolated by filtration, and washed with methanol to provide the product shown in the table below. [0726]
  • Examples 147-150
  • [0727]
    Figure US20040147543A1-20040729-C00200
    Example Boronic Acid or Ester R3
    147 trans-2-Phenylvinylboronic acid
    Figure US20040147543A1-20040729-C00201
    148 Pyridine-3-boronic acid
    Figure US20040147543A1-20040729-C00202
    149 3-(Methylsulfonylamino)phenylboronic acid
    Figure US20040147543A1-20040729-C00203
    150 5-(tert-Butyldimethylsilanyloxymethyl) pyridine-3-boronic acid
    Figure US20040147543A1-20040729-C00204
  • Examples 147-150
  • [0728]
    mp
    Example Name Form (° C.) Anal.
    147 1-(4-Amino-2- Pale 217-218 Calcd for C25H28N4O2:
    ethoxymethyl-8-styryl-1H- yellow C, 72.09; H, 6.78; N,
    imidazo[4,5-c]quinolin-1- powder 13.45. Found: C,
    yl)-2-methylpropan-2-ol 71.71; H, 6.97; N,
    13.46.
    148 1-[4-Amino-2- White 222-223 Calcd for C22H25N5O2:
    ethoxymethyl-8-(pyridin-3- crystals C, 67.50; H, 6.44; N,
    yl)-1H-imidazo[4,5- 17.89. Found: C,
    c]quinolin-1-yl]-2- 67.23; H, 6.55; N,
    methylpropan-2-ol 17.85.
    149 N-{3-[4-Amino-2- Off- 221-222 Calcd for
    ethoxymethyl-1-(2-hydroxy- white C24H29N5O4S.0.33H2O:
    2-methylpropyl)-1H- crystals C, 58.89; H, 6.11; N,
    imidazo[4,5-c]quinolin-8- 14.31. Found: C,
    yl]phenyl}methanesulfamide 58.81; H, 5.80; N,
    14.30.
    150 1-[4-Amino-2- White 230-232 Calcd for C23H27N5O3:
    ethoxymethyl-8-(5- powder C, 65.54; H, 6.46; N,
    hydroxymethylpyridin-3-yl)- 16.62. Found: C,
    1H-imidazo[4,5-c]quinolin- 65.25; H, 6.24; N,
    1-yl]-2-methylpropan-2-ol 16.65.
  • Example 151 1-(4-Amino-2-ethoxymethyl-8-phenethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol
  • [0729]
    Figure US20040147543A1-20040729-C00205
  • 1-(4-Amino-2-ethoxymethyl-8-styryl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (1.0 g, 2.4 mmol) was treated according to the method described in Example 123. The crude product was purified by flash column chromatography on silica gel (eluting with 95:5 dichloromethane:methanol) prior to recrystallization from methanol to provide 0.500 g of 1-(4-amino-2-ethoxymethyl-8-phenethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as white crystals, mp 175-176° C. [0730]
  • Anal. Calcd for C[0731] 25H30N4O2: C, 70.38; H, 7.30; N, 13.13. Found: C, 70.27; H, 7.26; N, 13.11.
  • Examples 152-156
  • Part A [0732]
  • A solution of tert-butoxy N-(4-aminobutyl)carbamate (15.38 g, 81.7 mmol) in dichloromethane (100 mL) was added dropwise over a period of 30 minutes to a solution of 7-bromo-4-chloro-3-nitroquinoline (74.3 mmol) and triethylamine (20.6 mL, 149 mmol) in dichloromethane (400 mL), and the reaction was stirred overnight at ambient temperature. The reaction was diluted with dichloromethane (500 mL), washed sequentially with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from isopropanol to provide tert-butyl [4-(7-bromo-3-nitroquinolin-4-ylamino)butyl]carbamate as a yellow solid. [0733]
  • Part B [0734]
  • A solution of sodium hydrosulfite (43.35 g, 249 mmol) and potassium carbonate (38.28 g, 277 mmol) in water (300 mL) was added to a mixture of tert-butyl [4-(7-bromo-3-nitroquinolin-4-ylamino)butyl]carbamate (24.3 g, 55.3 mmol) and 1,1′-diethyl-4,4′-bipyridinium dibromide (1.03 g, 2.76 mmol) in dichloromethane (368 mL) and water (40 mL), and the reaction was stirred overnight at ambient temperature. The reaction mixture was filtered through a layer of CELITE filter aid. The aqueous filtrate was extracted with dichloromethane, and the combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 22.4 g of tert-butyl [4-(3-amino-7-bromoquinolin-4-ylamino)butyl]carbamate as a brown powder. [0735]
  • Part C [0736]
  • tert-Butyl [4-(3-amino-7-bromoquinolin-4-ylamino)butyl]carbamate (24.3 g, 59.4 mmol) was treated with ethoxyacetyl chloride (7.28 g, 59.4 mmol) according to the method described in Part C of Examples 125-135. [0737]
  • Part D [0738]
  • A solution of the material from Part C and triethylamine (33.1 mL, 238 mmol) in ethanol (295 mL) was heated at reflux for two hours. The reaction was then allowed to cool to ambient temperature, and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane, and the resulting solution was washed sequentially with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (eluting sequentially with 90:10 and 85:15 chloroform:CMA) to provide 23.6 g of tert-butyl [4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate as a tan solid. [0739]
  • Part E [0740]
  • Concentrated hydrochloric acid (15.6 mL, 0.194 mol) was added to a solution of tert-butyl [4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate (23.2 g, 48 mmol) in ethanol, and the reaction was heated at reflux for 20 minutes. A precipitate formed, and the reaction was allowed to cool to ambient temperature overnight. The solid was isolated by filtration, washed with ethanol, and dissolved in water. The solution was washed with dichloromethane and then made basic with the addition of 50% aqueous sodium hydroxide. The basic solution was extracted with dichloromethane (3×300 mL), and the combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 17 g of 4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butylamine as an off-white solid. [0741]
  • Part F [0742]
  • 3-Chloropropanesulfonyl chloride (5.45 mL, 44.8 mmol) was added dropwise over a period of four minutes to a solution of 4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butylamine (16.9 g, 44.8 mmoL) and triethylamine (9.42 mL, 67.6 mmol) in dichloromethane (300 mL), and the reaction was stirred at ambient temperature for 30 minutes. The reaction was poured into water, and the organic layer was washed with brine and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was dissolved in N,N-dimethylformamide (DMF) (300 mL), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (10.1 mL, 67.6 mmol) was added. The reaction was stirred overnight at ambient temperature under a nitrogen atmosphere. Additional DBU (5 mL) was added, and the reaction was stirred for an additional four hours. The solvent was removed under reduced pressure, and the residue was dissolved in dichloromethane. The resulting solution was washed with water (2×200 mL) and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 7-bromo-1-[4-(1,1-dioxidoisothiazolidin-2-yl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline as an oil. [0743]
  • Part G [0744]
  • 7-Bromo-1-[4-(1,1-dioxidoisothiazolidin-2-yl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline was oxidized and then aminated according to the methods described in Parts H and I of Example 1. The oxidation was carried out in chloroform, and several equivalents of 3-chloroperoxybenzoic acid were used. The product from amination was purified by column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 98:2 to 85:15) followed by recrystallization from acetonitrile to provide 7-bromo-1-[4-(1,1-dioxidoisothiazolidin-2-yl)-2-ethoxymethyl-1H-imidazo [4,5-c] quinolin-4-amine ethyl-1H-imidazo[4,5-c]quinolin-4-amine [0745]
  • Part H [0746]
  • 7-Bromo-1-[4-(1,1-dioxidoisothiazolidin-2-yl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine and the boronic acid or boronic acid ester from the table below were coupled according to the general procedure described in Part J of Example 1. The reaction was heated at reflux until an analysis by HPLC indicated the reaction was complete. The work-up procedure described in Part F of Examples 125-135 was followed, and the crude product was purified by column chromatography on silica gel (eluting with a gradient of chloroform:CMA) followed by recrystallization using the solvent indicated in the table below. [0747]
  • For Example 155, the reaction was heated at reflux for three hours. Following chromatographic purification, the residue was deprotected according to the method described in Example 144, purified by column chromatography, and recrystallized from acetonitrile. [0748]
  • For Example 156, the coupling was carried out using tri(ortho-tolyl)phosphine instead of triphenylphosphine. [0749]
  • Examples 152-156
  • [0750]
    Figure US20040147543A1-20040729-C00206
    Recrystallization
    Example Boronic acid or ester solvent R3
    152 Phenylboronic acid Acetonitrile
    Figure US20040147543A1-20040729-C00207
    153 Pyridine-3-boronic acid 1,3- propanediol cyclic ester Isopropanol
    Figure US20040147543A1-20040729-C00208
    154 Pyridine-4-boronic acid pinacol ester Methanol then Isopropanol
    Figure US20040147543A1-20040729-C00209
    155 5-(tert- Butyldimethylsilanyloxymethyl) pyridine-3-boronic acid Acetonitrile
    Figure US20040147543A1-20040729-C00210
    156 3-(Hydroxymethyl)phenylboronic acid Acetonitrile (twice)
    Figure US20040147543A1-20040729-C00211
  • Example 152 1-[4-(1,1-Dioxidoisothiazolidin-2-yl)butyl]-2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-4-amine
  • The product was obtained as white crystals, mp 167-168.5° C. [0751]
  • [0752] 13C NMR (75MHz, DMSO-d6) δ 152.3, 148.9, 145.6, 140.1, 138.5, 132.8, 129.0, 127.4, 126.7, 126.4, 123.8, 121.0, 120.1, 113.8, 65.4, 64.1, 46.5, 46.1, 45.1, 43.8, 27.2, 24.3, 18.3, 14.9;
  • MS (APCl) m/z 494.2213 (494.2226 calcd for C[0753] 26H31N5O3S, M+H);
  • Anal. Calcd for C[0754] 26H31N5O3S: C, 63.26; H, 6.33; N, 14.19; S, 6.50. Found: C, 62.66; H, 6.34; N, 14.10; S, 6.45.
  • Example 153 1-[4-(1,1-Dioxidoisothiazolidin-2-yl)-butyl]-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine
  • The product was obtained as white, flocculent crystals, mp 171-173° C. [0755]
  • Anal. Calcd for C[0756] 25H30N6O3S: C, 60.71; H, 6.11; N, 16.99. Found: C, 60.56; H, 6.18; N, 16.92.
  • Example 154 1-[4-(1,1-Dioxidoisothiazolidin-2-yl)-butyl]-2-ethoxymethyl-7-(pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-4-amine
  • The product was obtained as a white, crystalline solid, mp 186-187.5° C. [0757]
  • Anal. Calcd for C[0758] 25H30N6O3S: C, 60.71; H, 6.11; N, 16.99; S, 6.48. Found: C, 60.36; H, 6.38; N, 16.88; S, 6.42.
  • Example 155 (5-{4-Amino-1-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-7-yl}pyridin-3-yl)methanol
  • The product was obtained as a white, powdery solid, mp 184.5-186° C. [0759]
  • Anal. Calcd for C[0760] 26H32N6O4S: C, 59.52; H, 6.15; N, 16.02; S, 6.11. Found: C, 59.53; H, 6.01; N, 16.06; S, 6.04.
  • Example 156 (5-{4-Amino-1-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-7-yl}phenyl)methanol
  • The product was obtained as a white powder, mp 158-161° C. [0761]
  • [0762] 13C NMR (75MHz, DMSO-d6) δ 152.3, 148.9, 145.4, 143.3, 139.9, 138.7, 132.9, 46.5, 46.1, 45.1, 43.8, 27.2, 24.3, 18.3, 14.9; 46.5, 46.1, 45.1, 43.8, 27.2, 24.3, 18.3, 14.9;
  • MS (APCl) m/z 524.2 (524.2 calcd for C[0763] 27H33N5O4S, M+H);
  • Anal. Calcd for C[0764] 27H33N5O4S.0.3H2O: C, 61.93; H, 6.35; N, 13.37; S, 6.12.
  • Found: C, 61.51; H, 6.78; N, 13.24; S, 6.12. [0765]
  • Example 157 tert-Butyl {4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazol[4,5-c]quinolin-1-yl]butyl}carbamate
  • [0766]
    Figure US20040147543A1-20040729-C00212
  • tert-Butyl [4-(7-bromo-2-ethoxymethyl-1H-imidazo [4,5-c]quinolin-1-yl)butyl]carbamate was oxidized and aminated according to the methods described in Parts H and I of Example 1 to afford tert-butyl [4-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate, which was coupled with 3-pyridylboronic acid according to the method described in Part J of Example 1. The reaction was heated at reflux for four hours, and the work-up procedure described in Part F of Examples 125-135 was followed. The crude product was recrystallized from acetonitrile (1 mL/g) to provide tert-butyl {4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}carbamate as a white solid, mp 117-119° C. [0767]
  • Anal. Calcd for C[0768] 27H34N6O3: C, 64.33; H, 7.10; N, 16.67. Found: C, 64.35; H, 7.42; N, 16.71.
  • Example 158 tert-Butyl {4-[4-amino-2-propyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}carbamate
  • [0769]
    Figure US20040147543A1-20040729-C00213
  • tert-Butyl [4-(3-amino-7-bromoquinolin-4-ylamino)butyl]carbamate was treated with butyryl chloride and cyclized according to the methods described in Part C and D of Examples 125-135. The resulting product, tert-butyl [4-(7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate was oxidized and aminated according to the methods described in Parts H and I of Example 1 to afford tert-butyl [4-(4-amino-7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate, which was coupled with 3-pyridylboronic acid according to the method described in Part J of Example 1. The reaction was heated at reflux for four hours, and the work-up procedure described in Part F of Examples 125-135 was followed. The crude product was recrystallized from toluene (1 mL/g) to provide tert-butyl {4-[4-amino-2-propyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}carbamate as a tan powder, mp 136-138° C. [0770]
  • Anal. Calcd for C[0771] 27H34N6O2: C, 65.83; H, 7.37; N, 17.06. Found: C, 65.92; H, 7.61; N, 16.92.
  • Examples 159-161
  • Part A [0772]
  • 7-Bromo-4-chloro-3-nitroquinoline (39.85 g, 138.6 mmol) was reacted with 2,2-dimethyl-1,3-dioxolane-4-methanamine (20.0 g, 152 mmol) according to the method described in Part A of Examples 125-135 to provide 48.35 g of (7-bromo-3-nitroquinolin-4-yl)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl)amine as a yellow solid. The product was not recrystallized. [0773]
  • Part B [0774]
  • The methods described in Parts B, C, and D of Examples 152-156 were used to convert (7-bromo-3-nitroquinolin-4-yl)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl)amine to 7-bromo-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline, which was obtained as an off-white solid, mp 138-140° C. In Part B, 1,1′-di-n-octyl-4,4′-bipyridinium dibromide was used instead of 1,1′-diethyl-4,4′-bipyridinium dibromide. Triethylamine (1.1 equivalents) was added in Part C. [0775]
  • Anal. Calcd for C[0776] 19H22BrN3O3: C, 54.30; H, 5.28; N, 10.00. Found: C, 54.07; H, 5.25; N, 9.90.
  • Part C [0777]
  • 7-Bromo-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline was oxidized and then aminated according to the methods described in Parts H and I of Example 1. The oxidation product was not recrystallized. The product from amination was purified by column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 95:5 to 85:15) followed by recrystallization from acetonitrile to provide 7- bromo-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 174-175° C. [0778]
  • Anal. Calcd for C[0779] 19H23BrN4O3: C, 52.42; H, 5.33; N, 12.87. Found: C, 52.41; H, 5.25; N, 12.81.
  • Part D [0780]
  • 7-Bromo-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine and the boronic acid or ester from the table below were coupled according to the method described in Examples 118-121. The work-up procedure described in Part F of Examples 125-135 was followed. For Examples 159 and 160, the crude product was purified by flash chromatography (eluting with a gradient of chloroform:CMA) followed by recrystallization from the solvent indicated in the table below. For Example 161, the crude product was dissolved in hot methanol, filtered, concentrated under reduced pressure, triturated with ethyl acetate, isolated by filtration, and then recrystallized from methanol. [0781]
  • Examples 159-161
  • [0782]
    Figure US20040147543A1-20040729-C00214
    Recrystallization
    Example Boronic acid or ester solvent R3
    159 Pyridine-3-boronic acid 1,3- propanediol cyclic ester Acetonitrile (twice)
    Figure US20040147543A1-20040729-C00215
    160 4- (Hydroxymethyl)phenylboronic acid Ethanol
    Figure US20040147543A1-20040729-C00216
    161 Phenylboronic acid Methanol
    Figure US20040147543A1-20040729-C00217
    Example Name Form mp Anal.
    159 1-[(2,2-Dimethyl-1,3- dioxolan-4-yl)methyl]-2- ethoxymethyl-7-(pyridin-3- yl)-1H-imidazo[4,5- c]quinolin-4-amine White crystals 181-182° C. Calcd for C24H27N5O3: C, 65.65; H, 6.33; N, 15.95. Found: C, 65.77; H, 6.33; N, 15.96.
    160 1-[(2,2-Dimethyl-1,3- dioxolan-4-yl)methyl]-2- ethoxymethyl-7-(4- hydroxymethyiphenyl)-1H- imidazo[4,5-c]quinolin-4- amine Off- white crystals 219-220° C. Calcd for C26H30N4O4: C, 67.51; H, 6.54; N, 12.11. Found: C, 67.47; H, 6.21; N, 11.98.
    161 1-[(2,2-Dimethyl-1,3- dioxolan-4-yl)methyl]-2- ethoxymethyl-7-phenyl-1H- imidazo[4,5-c]quinolin-4- amine Light yellow crystals 168-170° C. Calcd for C25H28N4O3: C, 69.42; H, 6.53; N, 12.95. Found: C, 69.37; H, 6.62; N, 13.04.
  • Example 162 3-[4-Amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]propane-1,2-diol
  • [0783]
    Figure US20040147543A1-20040729-C00218
  • Hydrochloric acid (12 mL of 1 N) was added to a solution of 1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (0.75 g, 1.73 mmol) in THF, and the reaction was stirred overnight at ambient temperature. The THF was removed under reduced pressure, and 1% aqueous sodium hydroxide was added to the remaining solution to adjust to pH 9. A precipitate formed, was isolated by filtration, washed with water, and dried in an oven at 60° C. to provide 0.61 g of 3-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]propane-1,2-diol as a white solid, mp 218-220° C. [0784]
  • Anal. Calcd for C[0785] 21H23N5O3: C, 62.68; H, 6.01; N, 17.40. Found: C, 62.58; H, 5.99; N, 17.29.
  • Examples 163-175
  • Part A [0786]
  • 7-Bromo-4-chloro-3-nitroquinoline (29.54 g, 102.7 mmol) was reacted with 3-methoxy propyl amine (10.07 g, 113.0 mmol) according to the method described in Part A of Examples 125-135 to provide 32.9 g of (7-bromo-3-nitroquinolin-4-yl)-(3-methoxypropyl)amine as a yellow solid. The product was not recrystallized. [0787]
  • Part B [0788]
  • The methods described in Parts B, C, and D of Examples 152-156 were used to convert (7-bromo-3-nitroquinolin-4-yl)-(3-methoxypropyl)amine to 7-bromo-2-ethoxymethyl-1-(3-methoxypropyl)-1H-imidazo[4,5-c]quinoline, which was obtained as a white solid. In Part B, 1,1′-di-n-octyl-4,4′-bipyridinium dibromide was used instead of 1,1′-diethyl-4,4′-bipyridinium dibromide. Triethylamine (1.1 equivalents) was added in Part C. The chromatographic purification in Part D was carried out using ethyl acetate:acetone as the eluent. [0789]
  • Part C [0790]
  • 7-Bromo-2-ethoxymethyl-1-(3-methoxypropyl)-1H-imidazo[4,5-c]quinoline was oxidized and then aminated according to the methods described in Parts H and I of Example 1. The oxidation product was not recrystallized. The product from amination was purified as described in Part C of Examples 159-161 to provide 7-bromo-2-ethoxymethyl-1-(3-methoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine as off-white crystals. [0791]
  • Part D [0792]
  • 7-Bromo-2-ethoxymethyl-1-(3-methoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine and the boronic acid or ester from the table below were coupled according to the method described in Examples 118-121 or in Part J of Example 1. For Example 159, the product was isolated as a solid and recrystallized from ethanol. For the remaining examples, the crude product was purified by flash chromatography (eluting with a gradient of chloroform:CMA) followed by recrystallization from the solvent indicated in the table below. [0793]
  • For Example 167, following chromatographic purification the product was deprotected according to the method described in Example 144. The crude deprotected product was recrystallized from isopropanol and then from acetonitrile to provide the product shown in the table below. [0794]
  • Examples 163-175
  • [0795]
    Figure US20040147543A1-20040729-C00219
    Recrystallization
    Ex. Boronic acid or ester solvent R3
    163 Phenylboronic acid Isopropanol then acetonitrile
    Figure US20040147543A1-20040729-C00220
    164 Pyridine-3-boronic acid 1,3-propanediol cyclic ester Acetonitrile (twice)
    Figure US20040147543A1-20040729-C00221
    165 Pyridine-4-boronic acid pinacol ester Ethanol (twice)
    Figure US20040147543A1-20040729-C00222
    166 4-(Hydroxymethyl)phenylboronic acid Ethanol
    Figure US20040147543A1-20040729-C00223
    167 5-(tert- butyldimethylsilanyloxymethyl)pyridine- 3-boronic acid Isopropanol then Acetonitrile
    Figure US20040147543A1-20040729-C00224
    168 Furan-2-boronic acid Acetonitrile
    Figure US20040147543A1-20040729-C00225
    169 4-Chlorophenylboronic acid Ethanol (twice)
    Figure US20040147543A1-20040729-C00226
    170 4-(Morpholine-4- carbonyl)phenylboronic acid Ethanol
    Figure US20040147543A1-20040729-C00227
    171 3-(iso-Butylaminocarbonyl) phenylboronic acid Ethanol (twice)
    Figure US20040147543A1-20040729-C00228
    172 4-(Ethylsulfonyl)phenylboronic acid Ethanol
    Figure US20040147543A1-20040729-C00229
    173 4-(iso-Propoxyphenyl)boronic acid Acetonitrile
    Figure US20040147543A1-20040729-C00230
    174 3-(Morpholine-4- carbonyl)phenylboronic acid Acetonitrile
    Figure US20040147543A1-20040729-C00231
    175 3-(Pyrrolidine-1-carbonyl)phenylboronic acid Ethyl acetate
    Figure US20040147543A1-20040729-C00232
  • Examples 163-175
  • [0796]
    Example Name Form Mp (° C.) Anal.
    163 2-Ethoxymethyl-1-(3-methoxypropyl)-7- White 146-147 Calcd for C23H26N4O2: C, 70.75; H,
    phenyl-1H-imidazo[4,5-c]quinolin-4-amine crystals 6.71; N, 14.35. Found: C, 70.73; H,
    6.70; N, 14.34.
    164 2-Ethoxymethyl-1-(3-methoxypropyl)-7- White 151-152 Calcd for C22H25N5O2: C, 67.50; H,
    (pyridin-3-yl)-1H-imidazo[4,5-c]quinolin- crystals 6.44; N, 17.89. Found: C, 67.21; H,
    4-amine 6.46; N, 17.97.
    165 2-Ethoxymethyl-1-(3-methoxypropyl)-7- White, 225-226 Calcd for C22H25N5O2: C, 67.50; H,
    (pyridin-4-yl)-1H-imidazo[4,5-c]quinolin- crystalline 6.44; N, 17.89. Found: C, 67.29; H,
    4-amine solid 6.37; N, 17.64.
    166 2-Ethoxymethyl-1-(3-methoxypropyl)-7-(4- White, 228-229 Calcd for C24H28N4O3: C, 68.55; H,
    hydroxymethylphenyl)-1H-imidazo[4,5- crystalline 6.71; N, 13.32. Found: C, 68.36; H,
    c]quinolin-4-amine solid 6.86; N, 13.06.
    167 2-Ethoxymethyl-1-(3-methoxypropyl)-7-(5- White solid 198-199 Calcd for C23H27N5O3: C, 65.54; H,
    hydroxymethylpyridin-3-yl)-1H- 6.46; N, 16.62. Found: C, 65.41; H,
    imidazo[4,5-c]quinolin-4-amine 6.40; N, 16.63.
    168 2-Ethoxymethyl-7-(furan-2-yl)-1-(3- Off-white 144-145 Calcd for C21H24N4O3: C, 66.30; H,
    methoxypropyl)-1H-imidazo[4,5- solid 6.36; N, 14.73. Found: C, 65.96; H,
    c]quinolin-4-amine 6.16; N, 14.56.
    169 7-(4-Chlorophenyl)-2-ethoxymethyl-1-(3- White solid 188-190 Calcd for C23H25ClN4O2: C, 65.01;
    methoxypropyl)-1H-imidazo[4,5- H, 5.93; N, 13.18. Found: C, 64.72;
    c]quinolin-4-amine H, 5.93; N, 13.04.
    170 {4-[4-Amino-2-ethoxymethyl-1-(3- White solid 163-165 Calcd for C28H33N5O4: C, 66.78; H,
    methoxypropyl)-1H-imidazo[4,5- 6.61; N, 13.91. Found: C, 66.52; H,
    c]quinolin-7-yl]phenyl}morpholin-4- 6.59; N, 13.71.
    ylmethanone
    171 3-[4-Amino-2-ethoxymethyl-1-(3- Off-white 209-210 Calcd for C28H35N5O3: C, 68.69; H,
    methoxypropyl)-1H-imidazo[4,5- solid 7.21; N, 14.30. Found: C, 68.52; H,
    c]quinolin-7-yl]-N-(2- 7.44; N, 14.23.
    methylpropyl)benzamide
    172 7-[(4-Ethanesulfonyl)phenyl]-2- White solid 156-158 Calcd for C25H30N4O4S: C, 62.22;
    ethoxymethyl-1-(3-methoxypropyl)-1H- H, 6.27; N, 11.61. Found: C, 61.99;
    imidazo[4,5-c]quinolin-4-amine H, 5.98; N, 11.47.
    173 2-Ethoxymethyl-7-[4-(2-propoxy)phenyl]- Off-white 175-177 Calcd for C26H32N4O3: C, 69.62; H,
    1-(3-methoxypropyl)-1H-imidazo[4,5- crystals 7.19; N, 12.49. Found: C, 69.70; H,
    c]quinolin-4-amine 7.45; N, 12.60.
    174 {3-[4-Amino-2-ethoxymethyl-1-(3- Off-white 174-176 Calcd for C28H33N5O4: C, 66.78; H,
    methoxypropyl)-1H-imidazo[4,5- crystals 6.61; N, 13.91. Found: C, 66.55; H,
    c]quinolin-7-yl]phenyl}morpholin-4- 6.53; N, 13.97.
    ylmethanone
    175 {3-[4-Amino-2-ethoxymethyl-1-(3- White solid 145-146 Calcd for C28H33N5O3.0.85HCl: C,
    methoxypropyl)-1H-imidazo[4,5- 64.85; H, 5.81; N, 6.58. Found: C,
    c]quinolin-7-yl]phenyl}pyrrolidin-1- 64.90; H, 5.74; N, 6.61.
    ylmethanone
  • Example 176 tert-Butyl 4-{[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidine-1-carboxylate
  • [0797]
    Figure US20040147543A1-20040729-C00233
  • Part A [0798]
  • 7-Bromo-4-chloro-3-nitroquinoline was treated according to the methods described in Parts A through D of Examples 152-156 using 1-(tert-butoxycarbonyl)-4-(aminomethyl)piperidine (Carceller, E. et al, [0799] J. Med. Chem., 39, 487-493 (1996)) in Part A. In Part B, 1,1′-di-n-octyl-4,4′-bipyridinium dibromide was used instead of 1,1′-diethyl-4,4′-bipyridinium dibromide. Triethylamine (1.1 equivalents) was added to the reaction in Part C. Following chromatographic purification in Part D (eluting with 95:5 chloroform:CMA), tert-butyl 4-[(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate was obtained as an off-white solid. A small portion of the product was recrystallized from acetonitrile to provide a white solid, mp 169-170° C.
  • Anal. Calcd for C[0800] 24H31BrN4O3: C, 57.26; H, 6.21; N, 11.13. Found: C, 57.31; H, 6.29; N, 11.07.
  • Part B [0801]
  • tert-Butyl 4-[(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate was oxidized and then aminated according to the methods described in Parts H and I of Example 1. The oxidation product was not recrystallized. The product from amination was purified as described in Part C of Examples 159-161 to provide tert-butyl 4-[(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate as a tan solid. [0802]
  • Part C [0803]
  • tert-Butyl 4-[(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate (12.79 g, 24.67 mmol) and pyrdine-3-boronic acid 1,3-propanediol cyclic ester (4.42 g, 27.14 mmol) were coupled according to the method described in Examples 118-121. The work-up procedure described in Part F of Examples 125-135 was followed. The crude product was recrystallized twice from ethyl acetate to provide 10.89 g of tert-butyl 4-{[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidine-1-carboxylate as an off-white solid, mp 197-198° C. [0804]
  • Anal. Calcd for C[0805] 29H36N6O3.0.5H2O: C, 66.26; H, 7.10; N, 15.99. Found: C, 66.47; H, 7.47; N, 16.00.
  • Example 177 2-Ethoxymethyl- -(piperidin-4-ylmethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine trihydrochloride
  • [0806]
    Figure US20040147543A1-20040729-C00234
  • Ethanolic hydrochloric acid (17.68 mL of 4.25 M) was added to a solution of tert-butyl 4-{[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidine-1-carboxylate (9.71 g, 18.8 mmol) in anhydrous ethanol, and the reaction was heated at reflux for two hours. A precipitate formed, and the reaction was allowed to cool to ambient temperature. The solid was isolated by filtration, washed with a small volume of cold ethanol, and dried under reduced pressure to provide 7.1 g of 2-ethoxymethyl-1-(piperidin-4-ylmethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine trihydrochloride as an off-white solid, mp >250° C. [0807]
  • Anal. Calcd for C[0808] 24H28N6O.3HCl.1.17H2O: C, 52.70; H, 6.14; N, 15.36. Found: C, 53.11; H, 6.48; N, 15.07.
  • Examples 178-181
  • A 0.02-0.03 M solution of 2-ethoxymethyl-1-(piperidin-4-ylmethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine trihydrochloride (1 equivalent) and triethylamine (5 equivalents) in the solvent indicated in the table below was cooled to 4° C. The reagent from the table below (1 equivalent) was added dropwise, and the reaction was allowed to warm to ambient temperature and stirred for between two and 24 hours. The reaction mixture was diluted with chloroform, and the resulting solution was washed sequentially with water, 4% aqueous sodium carbonate (2×), water, and brine and then concentrated under reduced pressure. For Examples 178, 179, and 181, the residue was purified by flash column chromatography on silica gel (eluting with chloroform:CMA) followed by recrystallization from the solvent indicated in the table below. For Example 180, the crude product was recystallized from ethyl acetate. The structures of the products are shown in the table. [0809]
  • Examples 178-181
  • [0810]
    Reaction Recrystallization
    Example Reagent solvent solvent R
    178 Methanesulfonyl chloride Chloroform Acetonitrile then ethyl acetate
    Figure US20040147543A1-20040729-C00235
    179 Isobutyryl chloride 1-Methyl-2- pyrrolidinone Ethyl Acetate
    Figure US20040147543A1-20040729-C00236
    180 4- Morpholinecarbonyl chloride Chloroform Ethyl acetate
    Figure US20040147543A1-20040729-C00237
    181 Palmitoyl chloride Chloroform Chloroform:hexanes
    Figure US20040147543A1-20040729-C00238
  • Examples 178-181
  • [0811]
    Mp
    Example Name Form (° C.) Anal.
    178 2-Ethoxymethyl-1-{[1- Off-white 254-255 Calcd for
    (methanesulfonyl)piperidin- powder C25H30N6O3S.
    4-yl]methyl}-7-(pyridin-3- 0.4 HCl: C,
    yl)-1H-imidazo[4,5- 58.97; H, 6.02; N,
    c]quinolin-4-amine 16.50; Cl, 2.78.
    Found: C, 58.94;
    H, 5.78; N, 16.34;
    Cl, 3.06.
    179 2-Ethoxymethyl-1-[(1- Beige 130-132 Calcd for
    isobutyrylpiperidin-4- powder C28H34N6O2.
    yl)methyl]-7-(pyridin-3-yl)- 0.375 H2O: C,
    1H-imidazo[4,5-c]quinolin- 68.16; H, 7.10; N,
    4-amine 17.03. Found: C,
    67.84; H, 7.14; N,
    16.82.
    180 2-Ethoxymethyl-1-{[1- Tan solid 224-225 Calcd for
    (morpholin-4- C29H35N7O3.
    ylcarbonyl)piperidin-4- 0.125 H2O: C,
    yl]methyl}-7-(pyridin-3-yl)- 65.49; H, 6.68; N,
    1H-imidazo[4,5-c]quinolin- 18.43. Found: C,
    4-amine 65.12; H, 6.40; N,
    18.19.
    181 2-Ethoxymethyl-1-[(1- Off-white 72-75 Calcd for
    palmitoylpiperidin-4- crystalline C40H58N6O2.0.1
    yl)methyl]-7-(pyridin-3-yl)- solid H2O: C, 73.15;
    1H-imidazo[4,5-c]quinolin- H, 8.93; N, 12.80.
    4-amine Found: C, 72.83;
    H, 8.84; N, 12.75
  • Example 182 2-Ethoxymethyl-7-(pyridin-3-yl)-1-{[1-(tetrahydrofuran-2-ylcarbonyl)piperidin-4-yl]methyl}-1H-imidazo[4,5-c]quinolin-4-amine
  • [0812]
    Figure US20040147543A1-20040729-C00239
  • A solution of 2-ethoxymethyl-1-(piperidin-4-ylmethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine trihydrochloride (1.0 g, 1.90 mmol) and triethylamine (1.35 mL, 9.50 mmol) in chloroform (80 mL) was cooled to 4° C. 2-Tetrahydrofuroic acid (0.243 g, 2.09 mmol) and 1-(3-dimethoxyaminopropyl)-3-ethylcarbodiimide hydrochloride (0.401 g, 2.09 mmol) were sequentially added, and the reaction was stirred for two hours. The reaction was incomplete as determined by thin layer chromatography (TLC) analysis. The reaction was cooled to 4° C., and 1-hydroxybenzotriazole (0.283 g, 2.09 mmol) was added. The reaction was allowed to warm to ambient temperature, stirred for 16 hours, and then diluted with chloroform (100 mL). The resulting solution was washed sequentially with water (100 mL), 4% aqueous sodium carbonate (2×100 mL), water (200 mL), and brine (150 mL); dried over sodium sulfate; filtered; and concentrated under reduced pressure. The residue was purified by HPFC followed by recrystallization from ethyl acetate to provide 0.68 g of 2-ethoxyrnethyl-7-(pyridin-3-yl)-1-{[1-(tetrahydrofuran-2-ylcarbonyl)piperidin-4-yl]methyl}-1H-imidazo[4,5-c]quinolin-4-amine as a white, crystalline solid, mp 191-192° C. [0813]
  • Anal. Calcd for C[0814] 29H34N6O3.0.3H2O: C, 66.98; H, 6.71; N, 16.16. Found: C, 66.87; H, 6.70; N, 15.77.
  • Example 183-186
  • Part A [0815]
  • 7-Bromo-4-chloro-3-nitroquinoline (35.26 g, 123.8 mmol) was treated with 1-(3-aminopropyl)pyrrolidin-2-one (19.1 mL, 136.2 mmol) according to the method described in Part E of Example 1 to provide 40.87 g of 1-[3-(7-bromo-3-nitroquinolin-4-ylamino)propyl]pyrrolidin-2-one as a yellow solid. [0816]
  • Part B [0817]
  • 1-[3-(7-Bromo3-nitroquinolin-4-ylamino)propyl]pyrrolidin-2-one was treated according to the methods described in Parts B, C, and D of Examples 152-156. 3-Methoxypropionyl chloride was used in Part C, and triethylamine (1.3 equivalents) was added to the reaction mixture. The crude product obtained in Part D was purified by flash chromatography on silica gel (eluting sequentially with 100:0 and 92.5:7.5 chloroform:methanol) followed by recrystallization from acetonitrile. The crystals were washed with acetonitrile and diethyl ether and dried in a vacuum oven at 60° C. to provide 1-{3-[7-bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one as a light grey solid. [0818]
  • Part C [0819]
  • 1-{3-[7-Bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one was oxidized and then aminated according to the methods described in Parts H and I of Example 1. The product from amination was recrystallized from isopropanol and then from ethanol. The crystals were washed with cold ethanol and diethyl ether and dried overnight in a vacuum oven at 60° C. to provide 1-{3-[4-amino-7-bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one as a white solid, mp 228-231° C. [0820]
  • Anal. Calcd for C[0821] 20H24N5O2Br: C, 53.82; H, 5.42; N, 15.69. Found: C, 53.48; H, 5.37; N, 15.45.
  • Part D [0822]
  • 1-{3-[4-Amino-7-bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one and the boronic acid or ester from the table below were coupled according to the method described in Examples 118-121. The work-up procedure described in Part F of Examples 125-135 was followed. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:00 to 70:30) followed by recrystallization from the solvent listed in the table below to provide the product shown in the table. [0823]
  • Examples 183-186
  • [0824]
    Figure US20040147543A1-20040729-C00240
    Recrystallization
    Example Boronic acid or ester solvent R3
    183 3-Pyridine boronic acid Ethanol
    Figure US20040147543A1-20040729-C00241
    184 Pyridine-4-boronic acid pinacol ester Acetonitrile
    Figure US20040147543A1-20040729-C00242
    185 3-(Hydroxymethyl)phenylboronic acid Ethanol
    Figure US20040147543A1-20040729-C00243
    186 [3- (Methylsulfonyl)aminophenyl]boronic acid Not used
    Figure US20040147543A1-20040729-C00244
  • Examples 183-186
  • [0825]
    Exam- Mp
    ple Name Form (° C.) Anal.
    183 1-{3-[4-Amino-2-(2- White 218- Calcd for
    methoxyethyl)-7-(pyridin- solid 221 C25H28N6O2: C,
    3-yl)-1H-imidazo[4,5- 67.55; H, 6.35;
    c]quinolin-1-yl]propyl} N, 18.91. Found:
    pyrrolidin-2-one C, 67.30; H,
    6.37; N, 18.79.
    184 1-{3-[4-Amino-2-(2- Off- 232- Calcd for
    methoxyethyl)-7- white 235 C25H28N6O2: C,
    (pyridin-4-yl)-1H- solid 67.55; H, 6.35;
    imidazo[4,5-c]quinolin-1- N, 18.91. Found:
    yl]propyl}pyrrolidin-2-one C, 67.18; H,
    6.49; N, 18.77.
    185 1-{3-[4-Amino-7-(3- Off- 184- Calcd for
    hydroxymethylphenyl)- white 187 C27H31N5O3.1.2
    2-(2-methoxyethyl)-1H- needles H2O: C, 65.49;
    imidazo[4,5- H, 6.80; N,
    c]quinolin-1-yl]propyl} 14.14. Found:
    pyrrolidin-2-one C, 65.46; H,
    6.82; N, 14.14.
    186 N-(3-{4-Amino-2-(2- White 210- Calcd for
    methoxyethyl)-1-[3-(2- powder 213 C27H32N6O4S: C,
    oxopyrrolidin-1- 60.43; H, 6.01;
    yl)propyl]-1H-imidazo[4,5- N, 15.66. Found:
    c]quinolin-7-yl} C, 60.17; H,
    phenyl)methanesulfonamide 6.15; N, 15.66.
  • Examples 187-190
  • Part A [0826]
  • 6-Bromo-4-chloro-3-nitroquinoline (50.62 g, 177.8 mmol), prepared from 4-bromoaniline according to the methods described in Parts A-D of Example 1, was treated with 1-(3-aminopropyl)pyrrolidin-2-one (27.5 mL, 196 mmol) according to the method described in Part E of Example 1 to provide 61.41 g of 1-[3-(6-bromo-3-nitroquinolin-4-ylamino)propyl]pyrrolidin-2-one as a solid. [0827]
  • Part B [0828]
  • 1-[3-(6-Bromo3-nitroquinolin-4-ylamino)propyl]pyrrolidin-2-one was treated according to the methods described in Parts B, C, and D of Examples 152-156. 3-Methoxypropionyl chloride was used in Part C. The crude product obtained in Part D was recrystallized from acetonitrile. The crystals were washed with cold acetonitrile and diethyl ether and dried in a vacuum oven at 60° C. to provide 1-{3-[8-bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one as a light grey solid. [0829]
  • Part C [0830]
  • 1-{3-[8-Bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one was oxidized and then aminated according to the methods described in Parts H and I of Example 1. The product from amination was recrystallized twice from isopropanol. The crystals were washed with cold isopropanol and dried in a vacuum oven at 60° C. to provide 1-{3-[4-amino-8-bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one as a white solid, mp 185-188° C. [0831]
  • Anal. Calcd for C[0832] 20H24N5O2Br: C, 53.82; H, 5.42; N, 15.69. Found: C, 53.67; H, 5.28; N, 15.45.
  • Part D [0833]
  • 1-{3-[4-Amino-8-bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one and the boronic acid or ester from the table below were coupled according to the method described in Examples 118-121. The reaction was heated at reflux overnight. The work-up procedure described in Part F of Examples 125-135 was followed. For Examples 1-3, the crude product was recrystallized from the solvent indicated in the table below. For Example 4, the crude product was purified by HPFCTM (eluting with chloroform:CMA in a gradient from 100:00 to 75:25) followed by recrystallization from the solvents listed in the table below to provide the product shown in the table. [0834]
  • Examples 187-190
  • [0835]
    Figure US20040147543A1-20040729-C00245
    Recrystallization
    Example Boronic acid or ester solvent R3
    187 Phenylboronic acid Isopropanol
    Figure US20040147543A1-20040729-C00246
    188 3-Pyridine boronic acid Ethanol (twice)
    Figure US20040147543A1-20040729-C00247
    189 3-Acetylphenyl boronic acid Acetonitrile
    Figure US20040147543A1-20040729-C00248
    190 Thianaphthene-3-boronic acid Propyl acetate then toluene
    Figure US20040147543A1-20040729-C00249
  • Examples 187-190
  • [0836]
    Mp
    Example Name Form (° C.) Anal.
    187 1-{3-[4-Amino-2-(2- Off- 207-210 Calcd for
    methoxyethyl)-8-phenyl- white C26H29N5O2.0.2H2O:
    1H-imidazo[4,5- solid C, 69.85; H, 6.63; N,
    c]quinolin-1- 15.67. Found: C, 69.51;
    yl]propyl}pyrrolidin-2- H, 7.00; N, 15.42.
    one
    188 1-{3-[4-Amino-2-(2- Yellow 221-224 Calcd for C25H28N6O2:
    methoxyethyl)-8-(pyridin- solid C, 67.55; H, 6.35; N,
    3-yl)-1H-imidazo[4,5- 18.91. Found: C, 67.30;
    c]quinolin-1- H, 5.99; N, 18.91.
    yl]propyl}pyrrolidin-2-
    one
    189 1-{3-[8-(3-Acetylphenyl)- Yellow 164-167 Calcd for
    4-amino-2-(2- solid C28H31N5O3.0.3H2O:
    methoxyethyl)-1H- C, 68.50; H, 6.49; N,
    imidazo[4,5-c]quinolin-1- 14.27. Found: C, 68.16;
    yl]propyl}pyrrolidin-2- H, 6.43; N, 14.37.
    one
    190 1-{3-[4-amino-8- White 202-205 Calcd for C28H29N5O2S:
    (benzo[b]thiophen-3-yl)- solid C, 67.31; H, 5.85; N,
    2-(2-methoxyethyl)-1H- 14.02. Found: C, 67.07;
    imidazo[4,5-c]quinolin-1- H, 5.66; N, 13.88.
    yl]propyl}pyrrolidin-2-
    one
  • Example 191 tert-Butyl 4-[(4-amino-2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate
  • [0837]
    Figure US20040147543A1-20040729-C00250
  • Part A [0838]
  • 4—Chloro-3-nitro-7-phenylquinoline (8.35 g, 29.3 mmol) was treated with 1-(tert-butoxycarbonyl)-4-(aminomethyl)piperidine (7.54 g, 35.2 mmol) according to the method described in Part A of Examples 152-156. The crude solid was triturated with water, isolated by filtration, sonicated with diethyl ether, isolated by filtration, and dried for four hours in a vacuum oven at 40° C. to provide 12.78 g of tert-butyl 4-[(3-nitro-7-phenylquinolin-4-ylamino)methyl]piperidine-1-carboxylate as a yellow solid, mp 153-154° C. [0839]
  • Part B [0840]
  • tert-Butyl 4-[(3-nitro-7-phenylquinolin-4-ylamino)methyl]piperidine-1-carboxylate was treated according to the methods described in Parts B-D of Example 152-156. In Part B, 1,1′-di-n-octyl-4,4′-bipyridinium dibromide was used instead of 1,1′-diethyl-4,4′-bipyridinium dibromide. Triethylamine (1.1 equivalents) was added to the reaction in Part C. The crude product from Part D was purified by flash column chromatography on silica gel (eluting with 95:5 chloroform:CMA) followed by recrystallization from dichloromethane:diethyl ether to provide tert-butyl 4-[(2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate as a white powder, mp 166-167° C. [0841]
  • Anal. Calcd for C[0842] 30H36N4O3: C, 71.97; H, 7.25; N, 11.19. Found: C, 71.86; H, 7.20; N, 11.11.
  • Part C [0843]
  • tert-Butyl 4-[(2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate was oxidized and then aminated according to the methods described in Parts H and I of Example 1. The oxidation product was not recrystallized. The product from amination was purified by column chromatography on silica gel (eluting with 90:10 chloroform:CMA) followed by recrystallization from ethyl acetate to provide tert-butyl 4-[(4-amino-2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate as a white powder, mp 194-195° C. [0844]
  • Anal. Calcd for C[0845] 30H37N5O3: C, 69.88; H, 7.23; N, 13.58. Found: C, 69.85; H, 7.16; N, 13.43.
  • Example 192 2-Ethoxymethyl-7-phenyl-1-(piperidin-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine
  • [0846]
    Figure US20040147543A1-20040729-C00251
  • tert-Butyl 4-[(4-amino-2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate (0.64 g) was deprotected according to the method described in Example 177. The crude solid was dissolved in water (10 mL), and ammonium hydroxide was added until the solution was basic. The mixture was then extracted with chloroform (2×10 mL), and the combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from acetonitrile and dried for 16 hours in a vacuum oven at 60° C. to provide 0.28 g of 2-ethoxymethyl-7-phenyl-1-(piperidin-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a white, crystalline solid, mp 142-143° C. [0847]
  • Anal. Calcd for C[0848] 25H29N5O.0.5H2O: C, 70.73; H, 7.12; N, 16.50. Found: C, 70.58; H, 7.24; N, 16.61.
  • Examples 193-195
  • 2-Ethoxymethyl-7-phenyl-1-(piperidin-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine dihydrochloride was prepared according to the method described in Example 177. A solution of 2-ethoxymethyl-7-phenyl-1-(piperidin- 4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine dihydrochloride (1.0 g, 2.05 mmol) and triethylamine (1.14 mL, 8.20 mmol) in dichloromethane (35 mL) was cooled to 4° C. The reagent from the table below (2.05 mmol) was added dropwise, and the reaction was allowed to warm to ambient temperature and stirred for between one and three hours. The reaction mixture was diluted with chloroform, and the resulting solution was washed sequentially with water, 4% aqueous sodium carbonate (2×), water, and brine and then concentrated under reduced pressure. The crude product was recystallized from the solvent listed in the table below to provide the compound shown in the table. [0849]
  • Example 193-195
  • [0850]
    Figure US20040147543A1-20040729-C00252
    Recrystallization
    Example Reagent solvent R
    193 Methanesulfonyl chloride Ethyl acetate
    Figure US20040147543A1-20040729-C00253
    194 Isobutyryl chloride Ethyl acetate then acetonitrile
    Figure US20040147543A1-20040729-C00254
    195 4- Morpholinecarbonyl chloride Ethyl acetate
    Figure US20040147543A1-20040729-C00255
  • Examples 193-195
  • [0851]
    Exam- Mp
    ple Name Form (° C.) Anal.
    193 2-Ethoxymethyl-1-{[1- White 224- Calcd for
    (methanesulfonyl)piperidin- solid 225 C26H31N5O3S:
    4-yl]methyl}-7- C, 63.26; H,
    phenyl-1H-imidazo[4,5- 6.33; N, 14.19.
    c]quinolin-4-amine Found: C, 62.99;
    H, 6.49; N,
    14.05.
    194 2-Ethoxymethyl-1-[(1- White, 156- Calcd for
    isobutyrylpiperidin-4- crys- 158 C29H35N5O2.0.5.
    yl)methyl]-7-phenyl-1H- talline H2O: C,
    imidazo[4,5-c]quinolin-4- solid 70.42; H, 7.34;
    amine N, 14.16.
    Found: C, 70.17;
    H, 7.49; N,
    14.13.
    195 2-Ethoxymethyl-1-{[1- White 208- Calcd for
    (morpholin-4- solid 209 C30H36N6O3: C,
    ylcarbonyl)piperidin-4- 68.16; H, 6.86;
    yl]methyl}-7-phenyl-1H- N, 15.90.
    imidazo[4,5-c]quinolin-4- Found: C, 67.82;
    amine H, 6.99; N,
    15.71.
  • Examples 196-198
  • Part A [0852]
  • 4-Chloro-3-nitro-7-phenylquinoline (6.0 g, 21 mmol) was treated with 2- phenoxyethylamine (3.18 g, 23.2 mmol) according to the method described in Part A of Examples 125-135. The crude solid was triturated with water (100 mL), isolated by filtration, sonicated with diethyl ether, isolated by filtration, and dried for two hours in a vacuum oven at 40° C. to provide 8.12 g of (3-nitro-7- phenylquinolin-4-yl)-(2-phenoxyethyl)amine as a yellow solid. Part B A solution of (3-nitro-7-phenylquinolin-4-yl)-(2-phenoxyethyl)amine (7.25 g, 18.8 mmol) in methanol (150 mL) was added to a Parr vessel charged with 5% platinum on carbon (0.84 g), and the reaction was placed under hydrogen pressure (50 psi, 3.4×10[0853] 5 Pa) for three hours. The reaction mixture was filtered through a layer of CELITE filter aid, and the filtrate was concentrated under reduced pressure, dissolved in toluene (2×25 mL), and concentrated under reduced pressure to provide N4-(2-phenoxyethyl)-7- phenylquinoline-3,4-diamine as a yellow semi-solid. Part C A modification of the method described in Part C of Examples 125-135 was followed. A 0.2 M solution of the material from Part B and triethylamine (1 equivalent) in dichloromethane was treated with the acid chloride (1 equivalent) indicated in the table below. Part D The material from Part C was cyclized according to the method described in Part D of Examples 152-156. The crude product was purified by flash chromatography on silica gel (eluting with 95:5 chloroform:CMA) followed by recrystallization from ethyl acetate or ethyl acetate:diethyl ether to provide the following products. Example 196: 2-Cyclopropylmethyl-1-(2-phenoxyethyl)-7-phenyl-1H- imidazo[4,5-c]quinoline was obtained as a white powder, mp 175-176° C. Anal. Calcd for C28H25N3O: C, 80.16; H, 6.01; N, 10.02. Found: C, 79.87; H, 5.92; N, 9.85.
  • Example 197: 2-Ethoxymethyl-1-(2-phenoxyethyl)-7-phenyl-1H-imidazo[4,5-c]quinoline was obtained as a yellow, crystalline solid, mp 137-138° C. Anal. Calcd for C[0854] 27H25N3O2: C, 76.57; H, 5.95; N, 9.92. Found: C, 76.60; H, 6.10; N, 9.66.
  • Example 198: 2-(4-Methoxybenzyl)-1-(2-phenoxyethyl)-7-phenyl-1H-imidazo[4,5-c]quinoline was obtained as a white, crystalline powder, mp 205-206° C. Anal. Calcd for C[0855] 32H27N3O2: C, 79.15; H, 5.60; N, 8.65. Found: C, 78.87; H, 5.65; N, 8.60.
  • Part E [0856]
  • The material from Part D was oxidized and then aminated according to the methods described in Parts H and I of Example 1. The oxidation product was not recrystallized. The product from amination was purified by column chromatography on silica gel (eluting with 95:5 or 90:10 chloroform:CMA) followed by recrystallization from ethyl acetate to provide the products shown in the table below. [0857]
  • Examples 196-198
  • [0858]
    Figure US20040147543A1-20040729-C00256
    Example Acid Chloride R2
    196 Cyclopropylacetyl chloride
    Figure US20040147543A1-20040729-C00257
    197 Ethoxyacetyl chloride
    Figure US20040147543A1-20040729-C00258
    198 4-Methoxyphenylacetyl chloride
    Figure US20040147543A1-20040729-C00259
  • Examples 196-198
  • [0859]
    Exam- Mp
    ple Name Form (° C.) Anal.
    196 2-Cyclopropylmethyl-1- White 188- Calcd for
    (2-phenoxyethyl)-7- solid 189 C28H26N4O: C,
    phenyl-1H-imidazo[4,5- 77.39; H, 6.03; N,
    c]quinolin-4-amine 12.89. Found: C,
    77.10; H, 6.03; N,
    12.85.
    197 2-Ethoxymethyl-1-(2- White, 159- Calcd for
    phenoxyethyl)-7-phenyl- crys- 160 C27H26N4O2: C,
    1H-imidazo[4,5- talline 73.95; H, 5.98; N,
    c]quinolin-4-amine solid 12.78. Found: C,
    73.72; H, 5.94; N,
    12.78.
    198 2-(4-Methoxybenzyl)-1- Fluffy, 197- Calcd for
    (2-phenoxyethyl)-7- white 198 C32H28N4O2: C,
    phenyl-1H-imidazo[4,5- powder 76.78; H, 5.64; N,
    c]quinolin-4-amine 11.19. Found: C,
    76.55; H, 5.75; N,
    11.12.
  • Example 199 N-{4-[4-Amino-2-(2-methoxyethyl)-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}methanesulfonamide
  • [0860]
    Figure US20040147543A1-20040729-C00260
  • Part A [0861]
  • Under a nitrogen atmosphere, a solution of tert-butyl N-(4-aminobutyl)carbamate (13.8 g, 73.4 mmol) and triethylamine (15.3 mL, 110 mmol) was cooled to 0° C. Methanesulfonyl chloride (6.3 mL, 81 mmol) was added, and the reaction was allowed to warm to ambient temperature and stirred overnight. Aqueous acetic acid (200 mL of 10%) was added. The organic layer was then separated and washed with water (200 mL), saturated aqueous sodium bicarbonate (200 mL), water (200 mL), and brine; dried over sodium sulfate; filtered; and concentrated under reduced pressure to provide 18.9 g of tert-butyl [4-(methanesulfonylamino)butyl]carbamate as an off-white solid. [0862]
  • Part B [0863]
  • A solution of hydrochloric acid in ethanol was added to a solution of tert-butyl [4-(methanesulfonylamino)butyl]carbamate (18.9 g, 71.1 mmol) in ethanol (100 mL), and the reaction was heated at 100° C. for two hours. The solvent was removed under reduced pressure. A mixture of dichloromethane:hexanes was added to the resulting oil and removed under reduced pressure; this process was repeated several times. The residue was dried for three days under vacuum to provide 14.3 g of N-(4-aminobutyl)methanesulfonamide hydrochloride as a tan solid. [0864]
  • Part C [0865]
  • N-(4-aminobutyl)methanesulfonamide hydrochloride (7.8 g, 39 mmol) was added to a suspension of 4-chloro-3-nitro-7-phenylquinoline (35 mmol) and triethylamine (8.0 g, 79 mmol) in NMP (80 mL), and the reaction was stirred at ambient temperature overnight. The resulting solution was poured into water (350 mL) to form a solid, which was isolated by filtration, washed with water, air-dried, and recrystallized from acetonitrile to provide 12.0 g of N-[4-(3-nitro-7-phenylquinolin-4-ylamino)butyl]methanesulfonamide as yellow plates. [0866]
  • Part D [0867]
  • The method described in Part B of Examples 125-135 was used to convert N-[4-(3-nitro-7-phenylquinolin-4-ylamino)butyl]methanesulfonamide (12.0 g, 29.0 mmol) to N-[4-(3-amino-7-phenylquinolin-4-ylamino)butyl]methanesulfonamide, which was isolated as a brown solid. [0868]
  • Part E [0869]
  • The material from Part D was treated according to the method described in Part A of Example 9. The crude product was recrystallized from methyl ethyl ketone and then purified twice by flash column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 95:5 to 75:25 and eluting with acetone:methanol in a gradient from 100:0 to 95:5). [0870]
  • Part F [0871]
  • N-{4-[2-(2-methoxyethyl)-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}methanesulfonamide was oxidized and then aminated according to the methods described in Parts H and I of Example 1. Both reactions were carried out in chloroform. The oxidation product was recrystallized from 5:1 acetonitrile:ethyl acetate and dried under vacuum overnight at 45° C. The amination product was recrystallized from acetonitrile and dried in a vacuum oven at 70° C. to provide N-{4-[4-amino-2-(2-methoxyethyl)-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}methanesulfonamide as a white solid, mp 201-202° C. [0872]
  • Anal. Calcd for C[0873] 24H29N5O3S: C, 61.65; H, 6.25; N, 14.98. Found: C, 61.55; H, 6.11; N, 15.01.
  • Example 200 N-[2-(4-Amino-7-phenyl-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide
  • [0874]
    Figure US20040147543A1-20040729-C00261
  • Part A [0875]
  • A solution of 1,2-diamino-2-methylpropane (9.3 mL, 88.9 mmol) and triethylamine (5.0 mL, 35.5 mmol) in dichloromethane (100 mL) was cooled to 0° C. A solution of 4-chloro-3-nitro-7-phenylquinoline (5.06 g, 17.8 mmol) in dichloromethane (50 mL) was added over a period of 45 minutes, and then the reaction was allowed to warm to ambient temperature. The solution was washed sequentially with water (2×100 mL) and brine (150 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide N[0876] 1-(3-nitro-7-phenylquinolin-4-yl)-2-methylpropane-1,2-diamine as an orange solid.
  • Part B [0877]
  • A solution of N[0878] 1-(3-nitro-7-phenylquinolin-4-yl)-2-methylpropane-1,2-diamine (5.85 g, 17.4 mmol) in dichloromethane (200 mL) was cooled to 0° C.
  • Triethylamine (3.6 mL, 26 mmol) and methanesulfonic anhydride (3.03, 17.4 mmol) were sequentially added. The reaction was allowed to warn to ambient temperature and stirred for two hours. Additional methanesulfonic anhydride (0.76 g, 4.4 mmol) was added, and the reaction was stirred overnight. A precipitate was present and was isolated by filtration, washed with water, and dried for two hours under high vacuum at 75° C. The filtrate was washed sequentially with water (2×100 mL) and brine (100 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloroethane. The two solids were combined to provide 5.26 g of N-[1,1-dimethyl-2-(3-nitro-7-phenylquinolin-4-ylamino)ethyl]methanesulfonamide as a yellow powder. [0879]
  • Part C [0880]
  • The method described in Part B of Examples 125-135 was used to convert N-[1,1-dimethyl-2-(3-nitro-7-phenylquinolin-4-ylamino)ethyl]methanesulfonamide (5.26 g, 12.6 mmol) to 4.53 g of N-[2-(3-amino-7-phenylquinolin-4-ylamino)-1,1-dimethylethyl]methanesulfonamide, which was isolated as a yellow-orange solid. [0881]
  • Part D [0882]
  • N-[2-(3-Amino-7-phenylquinolin-4-ylamino)-1,1-dimethylethyl]methanesulfonamide (2.20 g, 5.04 mmol) was treated with trimethyl orthobutyrate (0.90 mL, 5.5 mmol) according to the method described in Part G of Example 1. The chromatographic purification was carried out eluting with 92.5:7.5 dichloromethane:methanol to provide 1.8 g of N-[2-(7-phenyl-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide as a tan solid. [0883]
  • Part E [0884]
  • N-[2-(7-Phenyl-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide was oxidized and then aminated according to the methods described in Parts H and I of Example 1. The oxidation reaction was carried out in chloroform, and the product was not recrystallized. The product from amination was recrystallized from ethanol, and isolated by filtration. The solid was recrystallized from acetonitrile, and the crystals were dissolved in dichloromethane:methanol, concentrated under reduced pressure, and dried under high vacuum at 60° C. to provide N-[2-(4-amino-7-phenyl-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide as a white, crystalline solid, mp 135-141° C. [0885]
  • Anal. Calcd for C[0886] 24H29N5O2S: C, 63.83; H, 6.47; N, 15.51. Found: C, 63.48; H, 6.80; N, 15.34.
  • Example 201 N-[2-(4-Amino-2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide
  • [0887]
    Figure US20040147543A1-20040729-C00262
  • Part A [0888]
  • A modification of the method described in Part C of Examples 125-135 was used to treat N-[1,1-dimethyl-2-(3-amino-7-phenylquinolin-4-ylamino)ethyl]methanesulfonamide (2.33 g, 5.33 mmol) with ethoxyacetyl chloride (0.72 g, 5.87 mmol). Triethylamine (1.5 mL, 11 mmol) was added to the reaction, which was stirred overnight. [0889]
  • Part B [0890]
  • A solution of the material from Part A and triethylamine (1.5 mL, 11 mmol) in anhydrous toluene (100 mL) was heated at reflux overnight. The solvent was then removed under reduced pressure, and the residue was dissolved in dichloromethane (100 mL). The resulting solution was washed sequentially with 1% aqueous sodium carbonate (2×100 mL) and brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 95:5 dichloromethane:methanol) to provide 2.07 g of N-[2-(2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide as a yellow solid. [0891]
  • Part C [0892]
  • N-[2-(2-Ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulnamide was oxidized and then aminated according to the methods described in Parts H and I or Example 1. The oxidation reaction was carried out in chloroform, and the product was not recrystallized. The product from amination was recrystallized from acetonitrile, and the crystals were dissolved in dichloromethane:methanol, concentrated under reduced pressure, and dried in a vacuum oven to provide N-[2-(4-amino-2-ethoxymethyl- 7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide as a white powder, mp 239-242° C. [0893]
  • Anal. Calcd for C[0894] 24H29N5O2S.0.3H2O: C, 60.94; H, 6.31; N, 14.81. Found: C, 60.91; H, 6.03; N, 14.71.
  • Example 202 Cyclohexane N-[2-(4-amino-2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]carboxamide
  • [0895]
    Figure US20040147543A1-20040729-C00263
  • Part A [0896]
  • A solution of N[0897] 1-(3-nitro-7-phenylquinolin-4-yl)-2-methylpropane-1,2-diamine (3.56 g, 10.6 mmol) in dichloromethane (100 mL) was cooled to 0° C. Triethylamine (3.0 mL, 21 mmol) and cyclohexanecarbonyl chloride (1.55 mL, 11.6 mmol) were sequentially added. The reaction was allowed to warm to ambient temperature and stirred for two hours. The reaction was washed sequentially with water (2×100 mL) and brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 65:35 hexanes:ethyl acetate) to provide 3.33 g of cyclohexane N-[1,1-dimethyl-2-(3-nitro-7-phenylquinolin-4-ylamino)ethyl]carboxamide as a yellow solid.
  • Part B [0898]
  • The method described in Part B of Examples 125-135 was used to convert cyclohexane N-[1,1-dimethyl-2-(3-nitro-7-phenylquinolin-4-ylamino)ethyl]carboxamide (3.33 g, 7.46 mmol) to 3.06 g of cyclohexane N-[2-(3-amino-7-phenylquinolin-4-ylamino)-1,1-dimethylethyl]carboxamide, which was isolated as an orange solid. [0899]
  • Part C [0900]
  • Cyclohexane N-[2-(3-amino-7-phenylquinolin-4-ylamino)-1,1-dimethylethyl]carboxamide was treated according to the methods described in Parts A—C Example 201. The product from amination was purified by column chromatography on silica gel (eluting with 92.5:7.5 dichloromethane:methanol) followed by recrystallization from isopropanol. The crystals were dissolved in dichloromethane:methanol, concentrated under reduced pressure, and dried for two days under high vacuum at 65° C. to provide cyclohexane N-[2-(4-amino-2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]carboxamide as a white powder, mp 195-198° C. [0901]
  • Anal. Calcd for C[0902] 30H37N5O2.0.25H2O: C, 71.47; H, 7.50; N, 13.89. Found: C, 71.49; H, 7.54; N, 13.88.
  • Example 203 N-[2-(4-Amino-2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]-N′-cyclohexylurea
  • [0903]
    Figure US20040147543A1-20040729-C00264
  • Part A [0904]
  • A solution of N[0905] 1-(3-nitro-7-phenylquinolin-4-yl)-2-methylpropane-1,2-diamine (3.56 g, 10.6 mmol) in dichloromethane (100 mL) was cooled to 0° C. Cyclohexyl isocyanate (3.00 mL, 23.5 mmol) was added over the course of a day, and the reaction was stirred at ambient temperature for three days. The solvent was removed under reduced pressure. Xylenes (3 cx 100 mL) were added and removed under reduced pressure to provide N-cyclohexyl-N′-[1,1-dimethyl-2-(3-nitro-7-phenylquinolin-4-ylamino)ethyl]urea as a yellow solid.
  • Part B [0906]
  • The method described in Part B of Examples 125-135 was used to convert N-cyclohexyl—N′-[1,1-dimethyl-2-(3-nitro-7-phenylquinolin-4-ylamino)ethyl]urea (4.88 g, 10.6 mmol) to 4.35 g of N-[2-(3-amino-7-phenylquinolin-4-ylamino)-1,1-dimethylethyl]-N′-cyclohexylurea, which was isolated as an orange powder. [0907]
  • Part C [0908]
  • N-cyclohexyl—N′-[2-(3-amino-7-phenylquinolin-4-ylamino)-1,1-dimethylethyl]urea was treated according to the methods described in Parts A-C Example 201. The product from amination was recrystallized twice from ethanol. The crystals were dissolved in dichloromethane, and the resulting solution was washed sequentially with water (2×) and brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and dried for two days under high vacuum at 65° C. to provide N-[2-(4-amino-2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]-N′-cyclohexylurea as an off-white powder, mp 152-156° C. [0909]
  • Anal. Calcd for C[0910] 30H38N6O2: C, 70.01; H, 7.44; N, 16.33. Found: C, 69.78; H, 7.63; N, 16.24.
  • Examples 204 1-[3-(4-Amino-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]pyrrolidin-2-one
  • [0911]
    Figure US20040147543A1-20040729-C00265
  • Part A [0912]
  • 4-Chloro-3-nitro-7-phenylquinoline (3.51 g, 12.3 mmol) was treated with 1-(3-aminopropyl)pyrrolidin-2-one (2.3 mL, 16 mmol) according to the method described in Part E of Example I to provide 4.23 g of 1-[3-(3-nitro-7-phenylquinolin-4-ylamino)propyl]pyrrolidin-2-one as a yellow solid. [0913]
  • Part B [0914]
  • The method described in Part B of Examples 152-156 was used to convert 1-[3-(3-nitro-7-phenylquinolin-4-ylamino)propyl]pyrrolidin-2-one (4.25 g, 10.9 mmol) to 3.66 g of 1-[3-(3-amino-7-phenylquinolin-4-ylamino)propyl]pyrrolidin-2-one, which was obtained as a brown solid. In Part B, 1,1′-di-n-octyl-4,4′-bipyridinium dibromide was used instead of 1,1′-diethyl-4,4′-bipyridinium dibromide. [0915]
  • Part C [0916]
  • Triethyl orthoformate (2.50 mL, 15.0 mmol) was added to a solution of 1-[3-(3-amino-7-phenylquinolin-4-ylamino)propyl]pyrrolidin-2-one (3.59 g, 9.96 mmol) and pyridine hydrochloride (50 mg, 0.43 mmol) in anhydrous toluene (65 mL) and 1,2-dichloroethane (35 mL), and the reaction was heated at reflux overnight under a nitrogen atmosphere. The solution was then washed with saturated aqueous sodium carbonate (150 mL). The aqueous layer was extracted with dichloromethane (2×150 mL), and the combined organic fractions were washed with brine (150 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was dissolved in dichloromethane (5 mL), and diethyl ether (100 mL) was added to form a solid, which was isolated by filtration and dried in a vacuum oven at 60° C. to provide 2.51 g of a light brown solid. A portion of the product was recrystallized from 25:75 ethyl acetate:heptane and dried in a vacuum oven at 60° C. to provide 1-[3-(7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]pyrrolidin-2-one as a light brown solid, mp 138-141° C. [0917]
  • Anal. Calcd. for C[0918] 23H22N4O: C, 74.57; H, 5.99; N, 15.12. Found: C, 74.45; H, 6.17; N, 15.06.
  • Part D [0919]
  • 1-[3-(7-Phenyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]pyrrolidin-2-one was oxidized and then aminated according to the methods described in Parts H and I of Example 1. The product from amination was purified twice by column chromatography on silica gel (eluting with chloroform:CMA in gradients from 100:0 to 70:30). The resulting solid was washed with diethyl ether, recrystallized from acetonitrile, and dried in a vacuum oven at 60° C. to provide 1-[3-(4-amino-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]pyrrolidin-2-one as a light brown solid, mp 201-204° C. [0920]
  • Anal. Calcd. for C[0921] 23H23N5O: C, 71.67; H, 6.01; N, 18.17. Found: C, 71.64; H, 5.95; N, 18.48.
  • Example 205 1-[3-(4-Amino-2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]pyrrolidin-2-one
  • [0922]
    Figure US20040147543A1-20040729-C00266
  • Part A [0923]
  • 1-[3-(3-Amino-7-phenylquinolin-4-ylamino)propyl]pyrrolidin-2-one (2.21 g, 6.13 mmol) was treated with ethoxyacetyl chloride (0.95 mL, 8.76 mmol) according to the methods described in Parts C and D of Examples 152-156. Triethylamine (8.6 mmol) was added in Part C. The product from Part D was purified by column chromatography on silica gel (eluting with acetone and then chloroform:methanol in a gradient from 95:5 to 90:10) to provide 1.49 g of 1-[3-(2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]pyrrolidin-2-one as a brown solid. [0924]
  • Part B [0925]
  • 1-[3-(2-Ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]pyrrolidin-2-one was oxidized and then aminated according to the methods described in Parts H and I of Example 1. The product from amination was purified by column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 100:0 to 75:25) followed by recrystallization from acetonitrile and drying in a vacuum oven at 60° C. to provide 1-[3-(4-amino-2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]pyrrolidin-2-one as a light brown solid, mp 199-203° C. [0926]
  • Anal. Calcd. for C[0927] 26H29N5O2: C, 70.41; H, 6.59; N, 15.79. Found: C, 70.04; H, 6.55; N, 15.55.
  • Example 206 1-{3-[4-Amino-2-(2-methoxyethyl)-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one
  • [0928]
    Figure US20040147543A1-20040729-C00267
  • The methods described in Parts A of Example 204 were used to treat 1-[3-(3-amino-7-phenylquinolin-4-ylamino)propyl]pyrrolidin-2-one (1.19 g, 3.30 mmol) with 3-methoxypropionyl chloride (0.45 mL, 4.1 mmol) to afford 1-{3-[2-(2-methoxyethyl)-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one, which was oxidized and then aminated according to the methods described in Parts H and I of Example 1. The product from amination was recrystallized twice from acetonitrile and dried in a vacuum oven at 60° C. to provide 1-{3-[4-amino-2-(2-methoxyethyl)-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one as a light brown solid, mp 187-191° C. [0929]
  • Anal. Calcd. for C[0930] 26H29N5O2.0.13H2O: C, 70.05; H, 6.61; N, 15.71. Found: C, 69.66; H, 6.73; N, 15.82.
  • Examples 207-243
  • 7-Bromo-2-ethoxymethyl-1-(3-methoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine was coupled with the appropriate boronic acid or boronic acid ester according to the procedure described in Examples 20-65 and then purified by prep HPLC according to procedures described above. The table below shows the structure of the compound obtained in each example and the observed accurate mass for the isolated trifluoroacetate salt. Examples 207-243 [0931]
    Figure US20040147543A1-20040729-C00268
    Measured
    Mass
    Example R (M + H)
    207
    Figure US20040147543A1-20040729-C00269
    381.1920
    208
    Figure US20040147543A1-20040729-C00270
    397.1703
    209
    Figure US20040147543A1-20040729-C00271
    397.1696
    210
    Figure US20040147543A1-20040729-C00272
    405.2279
    211
    Figure US20040147543A1-20040729-C00273
    407.2063
    212
    Figure US20040147543A1-20040729-C00274
    407.2091
    213
    Figure US20040147543A1-20040729-C00275
    416.2078
    214
    Figure US20040147543A1-20040729-C00276
    416.2076
    215
    Figure US20040147543A1-20040729-C00277
    419.2453
    216
    Figure US20040147543A1-20040729-C00278
    419.2456
    217
    Figure US20040147543A1-20040729-C00279
    421.2240
    218
    Figure US20040147543A1-20040729-C00280
    421.2233
    219
    Figure US20040147543A1-20040729-C00281
    427.1955
    220
    Figure US20040147543A1-20040729-C00282
    433.2238
    221
    Figure US20040147543A1-20040729-C00283
    433.2244
    222
    Figure US20040147543A1-20040729-C00284
    433.2226
    223
    Figure US20040147543A1-20040729-C00285
    434.2203
    224
    Figure US20040147543A1-20040729-C00286
    435.2425
    225
    Figure US20040147543A1-20040729-C00287
    448.2346
    226
    Figure US20040147543A1-20040729-C00288
    449.2544
    227
    Figure US20040147543A1-20040729-C00289
    449.2560
    228
    Figure US20040147543A1-20040729-C00290
    451.2355
    229
    Figure US20040147543A1-20040729-C00291
    420.2405
    230
    Figure US20040147543A1-20040729-C00292
    381.2043
    231
    Figure US20040147543A1-20040729-C00293
    481.2441
    232
    Figure US20040147543A1-20040729-C00294
    484.1996
    233
    Figure US20040147543A1-20040729-C00295
    488.2650
    234
    Figure US20040147543A1-20040729-C00296
    490.2800
    235
    Figure US20040147543A1-20040729-C00297
    448.2330
    236
    Figure US20040147543A1-20040729-C00298
    420.2382
    237
    Figure US20040147543A1-20040729-C00299
    459.1323
    238
    Figure US20040147543A1-20040729-C00300
    421.2232
    239
    Figure US20040147543A1-20040729-C00301
    490.2826
    240
    Figure US20040147543A1-20040729-C00302
    435.2045
    241
    Figure US20040147543A1-20040729-C00303
    437.2012
    242
    Figure US20040147543A1-20040729-C00304
    451.2355
    243
    Figure US20040147543A1-20040729-C00305
    437.2174
  • Examples 244-323
  • A reagent from the table below, (0.064 mmol, 1.1 equivalents) was added to a test tube containing a solution of 2-ethoxymethyl-1-(piperidin-4-ylmethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine trihydrochloride (30 mg, 0.057 mmol) and N,N-diisopropylethylamine (0.048 mL, 0.27 mmol, 4.8 equivalents) in chloroform (2 mL). The test tube was capped placed on a shaker at ambient temperature overnight. One drop of deionized water was then added to each test tube, and the solvent was removed by vacuum centrifugation. For Example 323, the capped test tube was heated at 60° C. overnight in a sand bath, and then lithium trifluoromethanesulfonimide (3 mg) was added followed by shaking for an additional four hours. The products were purified by prep HPLC according to the methods described above. The table below shows the reagent used for each example, the structure of the resulting compound, and the observed accurate mass for the isolated trifluoroacetate salt. [0932]
  • Examples 244-323
  • [0933]
    Figure US20040147543A1-20040729-C00306
    Measured
    Mass
    Example Reagent R (M + H)
    244 Acetyl chloride
    Figure US20040147543A1-20040729-C00307
    459.2510
    250 Isobutyryl chloride
    Figure US20040147543A1-20040729-C00308
    487.2840
    245 Isovaleryl chloride
    Figure US20040147543A1-20040729-C00309
    501.2990
    246 Pentanoyl chloride
    Figure US20040147543A1-20040729-C00310
    501.2957
    247 Isoxazole-5-carbonyl chloride
    Figure US20040147543A1-20040729-C00311
    512.2435
    248 Benzoyl chloride
    Figure US20040147543A1-20040729-C00312
    521.2667
    249 Cyclohexanecarbonyl chloride
    Figure US20040147543A1-20040729-C00313
    527.3166
    250 m-Toluoyl chloride
    Figure US20040147543A1-20040729-C00314
    535.2848
    251 Phenylacetyl chloride
    Figure US20040147543A1-20040729-C00315
    535.2853
    252 Thiophene-2-acetyl chloride
    Figure US20040147543A1-20040729-C00316
    541.2407
    253 3-Cyclopentylpropionyl chloride
    Figure US20040147543A1-20040729-C00317
    541.3304
    254 Cinnamoyl chloride
    Figure US20040147543A1-20040729-C00318
    547.2837
    255 Hydrocinnamoyl chloride
    Figure US20040147543A1-20040729-C00319
    549.3021
    256 2-Methoxybenzoyl chloride
    Figure US20040147543A1-20040729-C00320
    551.2809
    257 m-Anisoyl chloride
    Figure US20040147543A1-20040729-C00321
    551.2786
    258 2-Chlorobenzoyl chloride
    Figure US20040147543A1-20040729-C00322
    555.2264
    259 3-Chlorobenzoyl chloride
    Figure US20040147543A1-20040729-C00323
    555.2272
    260 4-Chlorobenzoyl chloride
    Figure US20040147543A1-20040729-C00324
    555.2281
    261 trans-2-Phenyl-1- cyclopropanecarbonyl chloride
    Figure US20040147543A1-20040729-C00325
    561.2970
    262 Benzyloxyacetyl chloride
    Figure US20040147543A1-20040729-C00326
    565.2938
    263 1-Naphthoyl chloride
    Figure US20040147543A1-20040729-C00327
    571.2817
    264 2-Naphthoyl chloride
    Figure US20040147543A1-20040729-C00328
    571.2817
    265 Methyl 4-chlorocarbonylbenzoate
    Figure US20040147543A1-20040729-C00329
    579.2716
    266 3-(Trifluoromethyl)benzoyl chloride
    Figure US20040147543A1-20040729-C00330
    589.2557
    267 4-(Trifluoromethyl)benzoyl chloride
    Figure US20040147543A1-20040729-C00331
    589.2585
    268 2,4-Dichlorobenzoyl chloride
    Figure US20040147543A1-20040729-C00332
    589.1870
    269 3,4-Dichlorobenzoyl chloride
    Figure US20040147543A1-20040729-C00333
    589.1912
    270 4-(Trifluoromethoxy)benzoyl chloride
    Figure US20040147543A1-20040729-C00334
    605.2531
    271 Ethanesulfonyl chloride
    Figure US20040147543A1-20040729-C00335
    509.2364
    272 Isopropylsulfonyl chloride
    Figure US20040147543A1-20040729-C00336
    523.2523
    273 Dimethylsulfamoyl chloride
    Figure US20040147543A1-20040729-C00337
    524.2463
    274 Benzenesulfonyl chloride
    Figure US20040147543A1-20040729-C00338
    557.2380
    275 2-Thiophenesulfonyl chloride
    Figure US20040147543A1-20040729-C00339
    563.1921
    276 α-Toluenesulfonyl chloride
    Figure US20040147543A1-20040729-C00340
    571.2524
    277 m-Toluenesulfonyl chloride
    Figure US20040147543A1-20040729-C00341
    571.2509
    278 2-Cyanobenzenesulfonyl chloride
    Figure US20040147543A1-20040729-C00342
    582.2325
    279 3-Cyanobenzenesulfonyl chloride
    Figure US20040147543A1-20040729-C00343
    582.2301
    280 4-Cyanobenzenesulfonyl chloride
    Figure US20040147543A1-20040729-C00344
    582.2322
    281 trans-β-Styrenesulfonyl chloride
    Figure US20040147543A1-20040729-C00345
    583.2543
    282 4-Methoxybenzenesulfonyl chloride
    Figure US20040147543A1-20040729-C00346
    587.2435
    283 2-Chlorobenzenesulfonyl chloride
    Figure US20040147543A1-20040729-C00347
    591.1967
    284 3-Chlorobenzenesulfonyl chloride
    Figure US20040147543A1-20040729-C00348
    591.1970
    285 2,4-Difluorobenzenesulfonyl chloride
    Figure US20040147543A1-20040729-C00349
    593.2180
    286 2,6-Difluorobenzenesulfonyl chloride
    Figure US20040147543A1-20040729-C00350
    593.2167
    287 3-Nitrobenzenesulfonyl chloride
    Figure US20040147543A1-20040729-C00351
    602.2214
    288 8-Quinolinesulfonyl chloride
    Figure US20040147543A1-20040729-C00352
    608.2483
    289 3,4-Dimethoxybenzenesulfonyl chloride
    Figure US20040147543A1-20040729-C00353
    617.2534
    290 2- (Trifluoromethyl)benzenesulfonyl chloride
    Figure US20040147543A1-20040729-C00354
    625.2228
    291 3- (Trifluoromethyl)benzenesulfonyl chloride
    Figure US20040147543A1-20040729-C00355
    625.2214
    292 2,4-Dichlorobenzenesulfonyl chloride
    Figure US20040147543A1-20040729-C00356
    625.1567
    293 (1R)-(-)-10-Camphorsulfonyl chloride
    Figure US20040147543A1-20040729-C00357
    631.3110
    294 (1S)-(-)-10-Camphorsulfonyl chloride
    Figure US20040147543A1-20040729-C00358
    631.3090
    295 4-Biphenylsulfonyl chloride
    Figure US20040147543A1-20040729-C00359
    633.2662
    296 4- (Trifluoromethoxy)benzenesulfonyl chloride
    Figure US20040147543A1-20040729-C00360
    641.2178
    297 Isopropyl isocyanate
    Figure US20040147543A1-20040729-C00361
    502.2964
    298 n-Propyl isocyanate
    Figure US20040147543A1-20040729-C00362
    502.2924
    299 tert-Butyl isocyanate
    Figure US20040147543A1-20040729-C00363
    516.3080
    300 Dimethylcarbamyl chloride
    Figure US20040147543A1-20040729-C00364
    488.2809
    301 Phenyl isocyanate
    Figure US20040147543A1-20040729-C00365
    536.2817
    302 Cyclohexyl isocyanate
    Figure US20040147543A1-20040729-C00366
    542.3281
    303 Benzyl isocyanate
    Figure US20040147543A1-20040729-C00367
    550.2914
    304 m-Tolyl isocyanate
    Figure US20040147543A1-20040729-C00368
    550.2971
    305 o-Tolyl isocyanate
    Figure US20040147543A1-20040729-C00369
    550.2964
    306 p-Tolyl isocyanate
    Figure US20040147543A1-20040729-C00370
    550.2953
    307 3-Fluorophenyl isocyanate
    Figure US20040147543A1-20040729-C00371
    554.2717
    308 3-Cyanophenyl isocyanate
    Figure US20040147543A1-20040729-C00372
    561.2725
    309 4-Cyanophenyl isocyanate
    Figure US20040147543A1-20040729-C00373
    561.2756
    310 Phenethyl isocyanate
    Figure US20040147543A1-20040729-C00374
    564.3129
    311 1-Piperidinecarbonyl chloride
    Figure US20040147543A1-20040729-C00375
    528.3115
    312 3-Methoxyphenyl isocyanate
    Figure US20040147543A1-20040729-C00376
    566.2924
    313 4-Methoxyphenyl isocyanate
    Figure US20040147543A1-20040729-C00377
    566.2906
    314 2-Chlorophenyl isocyanate
    Figure US20040147543A1-20040729-C00378
    570.2419
    315 trans-2-Phenylcyclopropyl isocyanate
    Figure US20040147543A1-20040729-C00379
    576.3120
    316 3-Acetylphenyl isocyanate
    Figure US20040147543A1-20040729-C00380
    578.2910
    317 Benzoyl Isothiocyanate
    Figure US20040147543A1-20040729-C00381
    580.2478
    318 N-Methyl-N-phenylcarbamoyl chloride
    Figure US20040147543A1-20040729-C00382
    550.2927
    319 Methyl 3-Isocyanatobenzoate
    Figure US20040147543A1-20040729-C00383
    594.2820
    320 2-(Trifluoromethyl)phenyl isocyante
    Figure US20040147543A1-20040729-C00384
    604.2616
    321 3-(Trifluoromethyl)phenyl isocyante
    Figure US20040147543A1-20040729-C00385
    604.2638
    322 4-(Trifluoromethyl)phenyl isocyante
    Figure US20040147543A1-20040729-C00386
    604.2658
    323 Benzyl glycidyl ether
    Figure US20040147543A1-20040729-C00387
    581.3278
  • Examples 323-331
  • 1-(2-Amino-2-methylpropyl)-2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-4-amine was prepared from N[0934] 1-(3-nitro-7-phenylquinolin-4-yl)-2-methylpropane-1,2-diamine according to the methods described in Part C of Example 200 and Parts A—C of Example 201. A reagent from the table below, (0.051-0.058 mrnmol, 1.1 equivalents) was added to a test tube containing a solution of 1-(2-amino-2-methylpropyl)-2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-4-amine (20 mg, 0.051 mmol) and N,N-diisopropylethylamine (0.018 mL, 0.10 mmol, 2 equivalents) in chloroform (2 mL). The test tube was capped placed on a shaker at ambient temperature overnight. For Examples 324 and 327, the test tubes were then heated on a sand bath for two hours at 50° C. Ammonium hydroxide (2 drops) was added to the other reactions, and they were placed back on the shaker. The solvent was removed by vacuum centrifugation, and the products were purified by prep 15HPLC according to the methods described above. The table below shows the reagent used for each example, the structure of the resulting compound, and the observed accurate mass for the isolated trifluoroacetate salt.
  • Examples 324-331
  • [0935]
    Figure US20040147543A1-20040729-C00388
    Measured
    Exam- Mass
    ple Reagent R (M + H)
    324 Dimethylcarbamyl chloride
    Figure US20040147543A1-20040729-C00389
    475.2825
    325 Cyclohexyl isocyanate
    Figure US20040147543A1-20040729-C00390
    515.3126
    326 Methyl malonyl chloride
    Figure US20040147543A1-20040729-C00391
    490.2459
    327 Dimethylsulfamoyl chloride
    Figure US20040147543A1-20040729-C00392
    497.2338
    328 Phenylacetyl chloride
    Figure US20040147543A1-20040729-C00393
    508.2685
    329 3-Cyclopentylpropionyl chloride
    Figure US20040147543A1-20040729-C00394
    514.3140
    330 m-Anisolyl chloride
    Figure US20040147543A1-20040729-C00395
    524.2621
    331 3-Chlorobenzoyl chloride
    Figure US20040147543A1-20040729-C00396
    528.2164
  • Examples 332-362
  • Part A [0936]
  • tert-Butyl 4-[(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate (11.83 g, 22.82 mmol) was treated according to the method described in Example 177 to provide 9.73 g of 7-bromo-2-ethoxymethyl-1-(piperidin-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine dihydrochloride as a white, crystalline solid, mp >300° C. [0937]
  • Part B [0938]
  • The method described in Examples 178-181 was used to treat 7-bromo-2-ethoxymethyl-1-(piperidin-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine dihydrochloride (4.95 g, 10.1 mmol) with methanesulfonic anhydride (1.76 g, 10.1 mmol). The reaction was carried out in dichloromethane (150 mL). Following chromatographic purification (eluting with chloroform:CMA in a gradient from 100:0 to 90:10), the product was recrystallized from ethyl acetate to provide 2.37 g of 7-bromo-2-ethoxymethyl-1-{[1-(methanesulfonyl)piperidin-4-yl]methyl}-1H-imidazol[4,5-c]quinolin-4-amine as a white, crystalline solid, mp 233-234° C. [0939]
  • Anal. Calcd for C[0940] 20H26BrN5O3 S: C, 47.87; H, 5.34; N, 13.96. Found: C, 48.14; H, 5.28; N, 13.56.
  • Part C [0941]
  • 7-Bromo-2-ethoxymethyl-1-{[1-(methanesulfonyl)piperidin-4-yl]methyl}-1H-imidazo[4,5-c]quinolin-4-amine was coupled with the appropriate boronic acid or boronic acid ester according to the procedure described in Examples 20-65. The preoducts were purifed by prep HPLC according to the methods described above. The table below shows the structure of the compound obtained in each example and the observed accurate mass for the isolated trifluoroacetate salt. [0942]
  • Examples 332-362
  • [0943]
    Figure US20040147543A1-20040729-C00397
    Measured Mass
    Example R (M + H)
    332
    Figure US20040147543A1-20040729-C00398
    494.2178
    333
    Figure US20040147543A1-20040729-C00399
    500.1795
    334
    Figure US20040147543A1-20040729-C00400
    500.1746
    335
    Figure US20040147543A1-20040729-C00401
    524.2994
    336
    Figure US20040147543A1-20040729-C00402
    508.2383
    337
    Figure US20040147543A1-20040729-C00403
    508.2341
    338
    Figure US20040147543A1-20040729-C00404
    510.2195
    339
    Figure US20040147543A1-20040729-C00405
    510.2144
    340
    Figure US20040147543A1-20040729-C00406
    519.2164
    341
    Figure US20040147543A1-20040729-C00407
    524.2298
    342
    Figure US20040147543A1-20040729-C00408
    528.1834
    343
    Figure US20040147543A1-20040729-C00409
    530.1990
    344
    Figure US20040147543A1-20040729-C00410
    536.2293
    345
    Figure US20040147543A1-20040729-C00411
    536.2316
    346
    Figure US20040147543A1-20040729-C00412
    536.2313
    347
    Figure US20040147543A1-20040729-C00413
    538.2466
    348
    Figure US20040147543A1-20040729-C00414
    538.2468
    349
    Figure US20040147543A1-20040729-C00415
    593.2872
    350
    Figure US20040147543A1-20040729-C00416
    554.2466
    351
    Figure US20040147543A1-20040729-C00417
    566.2402
    352
    Figure US20040147543A1-20040729-C00418
    572.1982
    353
    Figure US20040147543A1-20040729-C00419
    584.2515
    354
    Figure US20040147543A1-20040729-C00420
    586.2136
    355
    Figure US20040147543A1-20040729-C00421
    587.2072
    356
    Figure US20040147543A1-20040729-C00422
    587.2101
    357
    Figure US20040147543A1-20040729-C00423
    591.2743
    358
    Figure US20040147543A1-20040729-C00424
    593.2916
    359
    Figure US20040147543A1-20040729-C00425
    618.2496
    360
    Figure US20040147543A1-20040729-C00426
    523.2438
    361
    Figure US20040147543A1-20040729-C00427
    591.2751
    362
    Figure US20040147543A1-20040729-C00428
    538.2087
  • Example 363 2-Ethoxymethyl-1-{2-[2-(methanesulfonyl)ethoxy]-2-methylpropyl}-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine
  • [0944]
    Figure US20040147543A1-20040729-C00429
  • Part A [0945]
  • A solution of methyl vinyl sulfone (3.0 g, 29 mmol) and 1-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (5.4 g, 14 mmol) in anhydrous THF (57 mL) was purged with nitrogen; solid sodium hydride (available as a 60% dispersion in mineral oil, 57 mg, 1.4 mmol) was added. The reaction was stirred for 70 minutes at ambient temperature, at which time an analysis by HPLC indicated a ratio of product to starting material of 3:1. The reaction mixture was combined with material from another run, and water (100 mL) was added. The aqueous layer was separated and extracted with ethyl acetate (100 mL, 50 mL). The combined organic fractions were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with 95:5 dichloromethane:methanol) to provide 7-bromo-2-ethoxymethyl-1-{2-[2-(methanesulfonyl)ethoxy]-2-methylpropyl}-1H-imidazo[4,5-c]quinoline. [0946]
  • Part B [0947]
  • A modification of the method described in Example 1 Part H was used to oxidize 7-bromo-2-ethoxymethyl-1-{2-[2-(methanesulfonyl)ethoxy]-2-methylpropyl}-1H-imidazo[4,5-c]quinoline (3.65 g, 7.53 mmol) with 3-chloroperoxybenzoic acid (2.2 g of 60% pure material, 7.53 mmol). The reaction was carried out in chloroform (38 mL) and allowed to proceed for one hour. The crude product was used without purification. [0948]
  • Part C [0949]
  • The material from Part B was aminated according to the method described in Part I of Example 1. The crude product was recrystallized from acetonitrile (35 mL), and the crystals were isolated by filtration, washed with acetonitrile, and dried for four hours under vacuum at 65° C. to provide 7-bromo-2-ethoxymethyl-1-{2-[2-(methanesulfonyl)ethoxy]-2-methylpropyl}-1H-imidazo[4,5-c]quinolin-4-amine as gold, crystalline plates, mp 198-201° C. [0950]
  • Anal. Calcd for C[0951] 20H27BrN4O4S: C, 48.10; H15.45; N, 11.22. Found: C, 47.96; H, 5.34; N, 11.20.
  • Part D [0952]
  • 7-Bromo-2-ethoxymethyl-1-{2-[2-(methanesulfonyl)ethoxy]-2-methylpropyl}-1H-imidazo[4,5-c]quinolin-4-amine (1.2 g, 2.4 mmol) and pyridine-3-boronic acid 1,3-propanediol cyclic ester (0.47 g, 2.9 mmol) were coupled according to the method described in Part J of Example 1. The work-up procedure used in Part F of Examples 125-135 was followed. The crude product was purified by column chromatography on silica gel (eluting sequentially with 95:5 and 90:10 dichloromethane:methanol) followed by recrystallization from acetonitrile (52 mL/g). The crystals were isolated by filtration, washed with acetonitrile, and dried for four hours under vacuum at 65° C. to provide 0.70 g of 2-ethoxymethyl- -{2-[2-(methanesulfonyl)ethoxy]-2-methylpropyl }-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as white, crystalline plates, mp 202-204° C. [0953]
  • Anal. Calcd for C[0954] 25H31N5O4S: C, 60.34; H, 6.28; N, 14.07. Found: C, 60.19; H, 6.45; N, 14.02.
  • Example 364 2-Ethoxymethyl-1-{2-[2-(methanesulfonyl)ethoxy]-2-methylpropyl}-7-(5-methoxypyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine
  • [0955]
    Figure US20040147543A1-20040729-C00430
  • 7-Bromo-2-ethoxymethyl-1-{2-[2-(methanesulfonyl)ethoxy]-2-methylpropyl}-1H-imidazo[4,5-c]quinolin-4-amine (1.1 g, 2.2 mmol) and pyridine-5-methoxy-3-boronic acid pinacol ester (0.63 g, 2.7 mmol) were coupled according to the method described in Part J of Example 1. The work-up procedure used in Part F of Examples 125-135 was followed. The crude product was purified by HPFC (eluting with dichloromethane:methanol in a gradient from 99:1 to 85:15) followed by trituration with ethyl acetate. The crystals were isolated by filtration and dried for four hours under vacuum at 65° C. to provide 0.1 g of 2-ethoxymethyl-1-{2-[2-(methanesulfonyl)ethoxy]-2-methylpropyl}-7-(5-methoxypyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, mp 186-188° C. [0956]
  • Anal. Calcd for C[0957] 26H33N5O5S: C, 59.18; H, 6.30; N, 13.27. Found: C, 58.96; H, 6.64; N, 13.09.
  • Example 365 Dimethyl 4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]butane-1-sulfonamide
  • [0958]
    Figure US20040147543A1-20040729-C00431
  • Part A [0959]
  • A modification of the method described in Part E of Example 1 was used to treat 7-bromo-4-chloro-3-nitroquinoline (20.0 g, 69.6 mmol) with 4-amino-1-butanol (6.9 mL, 76.5 mmol). The addition of 4-amino-1-butanol was carried out at ambient temperature. The product, 4-(7-bromo-3-nitroquinolin-4-ylamino)butan-1-ol (21.1 g) was isolated as a yellow solid and used without purification. [0960]
  • Part B [0961]
  • A suspension of 4-(7-bromo-3-nitroquinolin-4-ylamino)butan-1-ol (20.75 g, 61.0 mmol) in dichloromethane (220 mL) was cooled to 0° C.; thionyl chloride (4.90 mL, 67.1 mmol) was added dropwise over a period of ten minutes. The reaction was stirred at 0° C. for five minutes, allowed to warm to ambient temperature, and stirred overnight. Aqueous sodium bicarbonate (500 mL of 50%) was slowly added. The aqueous layer was separated and extracted with dichloromethane (3×100 mL). The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield an orange semi-solid. An analysis by LCMS indicated the presence of starting material, and the semi-solid was dissolved in dichloromethane (150 mL) and treated with thionyl chloride (3.0 mL) as described above. Following the work-up procedure, the crude product was purified by column chromatography on silica gel (eluting with dichloromethane:methanol in a gradient from 100:0 to 95:5) to provide 8.3 g of (7-bromo-3-nitroquinolin-4-yl)-(4-chlorobutyl)amine as a yellow solid. [0962]
  • Part C [0963]
  • A suspension of (7-bromo-3-nitroquinolin-4-yl)-(4-chlorobutyl)amine (8.05 g, 22.5 mmol) in methanol (250 mL) was cooled to 0° C.; a solution of sodium hydrosulfite (19.5 g, 112 mmol) in water (80 mL) was added dropwise over a period of 30 minutes. The reaction was stirred at ambient temperature for two hours and then concentrated under reduced pressure. The residue was partitioned between dichloromethane (300 mL) and aqueous sodium bicarbonate (150 mL of 50%). The aqueous layer was separated and extracted with dichloromethane (2×50 mL). The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 7.25 g of crude 7-bromo-N[0964] 4-(4-chlorobutyl)quinoline-3,4-diamine as a light brown semi-solid.
  • Part D [0965]
  • A modification of the method described in Part C of Examples 125-135 was used to treat 7-bromo-N[0966] 4-(4-chlorobutyl)quinoline-3,4-diamine (7.25 g, 22.1 mmol) with ethoxyacetyl chloride (2.76 mL, 24.3 mmol). After the reaction was stirred for one hour, it was concentrated under reduced pressure to provide N-[7-bromo-4-(4-chlorobutylamino)quinolin-3-yl]-2-eth6xyacetamide hydrochloride as a yellow solid.
  • Part E [0967]
  • Aqueous sodium hydroxide (16.6 mL of 2 M, 33.2 mmol) was added to a suspension of the material from Part D in ethanol (100 mL), and the reaction was heated to 60° C. over a period of 30 minutes and stirred at 60° C. for one hour. The reaction was allowed to cool to ambient temperature and then concentrated under reduced pressure. The residue was partitioned between water (150 mL) and dichloromethane (300 mL). The aqueous layer was separated and extracted with dichloromethane (2×75 mL). The combined organic fractions were washed with brine (100 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with ethyl acetate:chloroforn in a gradient from 20:80 to 100:0) to provide 4.46 g of 7-bromo-1-(4-chlorobutyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline as a tan solid. [0968]
  • Part F [0969]
  • Potassium thioacetate (1.70 g, 14.9 mmol) was added in one portion to a stirred solution of 7-bromo-1-(4-chlorobutyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline (5.37 g, 13.5 mmol) in DMF (65 mL), and the reaction was stirred at ambient temperature for 21 hours. The DMF was removed under reduced pressure, and the residue was partitioned between dichloromethane (300 mL) and water (150 mL). The organic layer was separated, washed with brine (120 mL), dried over magnesium sulfate, filtered, and concentrated to provide 6.09 g of thioacetic acid S-[4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]ester as a brown solid. [0970]
  • Part G [0971]
  • Nitrogen was bubbled through a solution of thioacetic acid S-[4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]ester (1.93 g, 4.42 mmol) in methanol (45 mL), and then sodium methoxide (2.5 mL of 25% by weight in methanol, 11.1 mmol) was added dropwise over a period of three minutes. The yellow solution was stirred at ambient temperature for one hour and then concentrated under reduced pressure. The residue was partitioned between dichloromethane (250 mL) and water (125 mL), and hydrochloric acid (˜3 mL of 2 M) was added to adjust the mixture to pH 7. The aqueous layer was separated and extracted with dichloromethane (50 mL); the combined organic fractions were washed with brine (100 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 1.73 g of 4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-thiol as a tan solid. [0972]
  • Part H [0973]
  • A solution of 4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-thiol (1.73 g, 4.39 mmol) in concentrated hydrochloric acid (7.5 mL) and water (5 mL) was cooled to 0° C. A solution of sodium chlorate (0.61 g, 5.7 mmol) in water (2.5 mL) was added dropwise with vigourous stirring over a period of three minutes. The reaction was stirred at 0° C. for 90 minutes then diluted with dichloromethane (50 mL). Aqueous potassium carbonate (8 mL of 6M) was slowly added to adjust the mixture to pH 5. Dichloromethane (100 mL) and water (75 mL) were added, and the reaction was allowed to warm to ambient temperature with stirring. The aqueous layer was separated and extracted with dichloromethane (3×40 mL). The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 1.61 g of 4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonyl chloride as a tan solid. [0974]
  • Part I [0975]
  • Dimethylamine hydrochloride (0.60 g, 7.3 mmol) and aqueous potassium carbonate (1.46 mL of 6 M, 8.7 mmol) were sequentially added to a stirred solution of 4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane- 1-sulfonyl chloride (1.61 g, 3.49 mmol) in dichloromethane (35 mL), and the reaction was stirred at ambient temperature for 80 minutes. Dichloromethane (180 mL) and aqueous sodium bicarbonate (60 mL) were added. The aqueous layer was separated and extracted with dichloromethane (2×40 mL); the combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 1.49 g of dimethyl 4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonamide as a tan solid. [0976]
  • Part J [0977]
  • 3-Chloroperoxybenzoic acid (0.126 g of 70% pure material, 0.73 mmol) was added in one portion to a stirred solution of dimethyl 4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonamide (0.30 g, 0.63 mmol) in chloroform (7 mL), and the solution was stirred for two hours at ambient temperature. Ammonium hydroxide (2 mL) and p-toluenesulfonyl chloride (0.15 g, 0.76 mmol) were sequentially added, and the mixture was stirred at ambient temperature for one hour. Dichloromethane (100 mL) was added, and the mixture was washed sequentially with 2 M aqueous sodium hydroxide (2×30 mL), saturated aqueous sodium bicarbonate (2×30 mL), and brine (30 mL); dried over magnesium sulfate; filtered; and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with ethyl acetate:ethanol in a gradient from 100:0 to 80:20) followed by recrystallization from dichloromethane:heptane. The crystals were dried for two hours under vacuum at 40° C. to provide 0.185 g of dimethyl 4-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonamide as a white solid, mp 193° C. [0978]
  • Anal. Calcd for Cl[0979] 9H26BrN5O3S: C, 47.11; H, 5.41; N, 14.46. Found: C, 46.85; H, 5.48; N, 14.14.
  • Part K [0980]
  • Dimethyl 4-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonamide (1.00 g, 2.06 mmol), which was prepared in a separate run, and pyridine-3-boronic acid 1,3-propanediol ester (0.40 g, 2.5 mmol) were coupled according to the method described in Part J of Example 1. The reaction was heated at reflux for 14 hours, and the work-up procedure used in Part F of Examples 125-135 was followed. The crude product was purified by column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 95:5 to 80:20) and then triturated sequentially with dichloromethane and methanol, isolated by filtration, and dried for two days under high vacuum at 140° C. to provide 0.695 g of dimethyl 4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]butane-1-sulfonamide as yellow needles, mp 205-206° C. [0981]
  • Anal. Calcd for C[0982] 24H30N6O3S: C, 59.73; H, 6.27; N, 17.41. Found: C, 59.49; H, 6.24; N, 17.36.
  • Example 366 Dimethyl 4-[4-amino-2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl]butane-1-sulfonamide
  • [0983]
    Figure US20040147543A1-20040729-C00432
  • Dimethyl 4-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonamide (0.66 g, 1.4 mmol) and phenyl boronic acid (0.20 g, 1.6 mmol) were coupled according to the method described in Part J of Example 1. The reaction was heated at reflux for 14 hours, and the work-up procedure used in Part F of Examples 125-135 was followed. The crude product was recrystallized from methanol and then purified by column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 100:0 to 90:10). The solid was then purified by HPFC to provide 0.14 g of dimethyl 4-[4-amino-2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl]butane-1-sulfonamide as Off-white needles, mp 207-208° C. [0984]
  • Anal. Calcd for C[0985] 25H31N5O3S: C, 61.56; H, 6.55; N, 14.36. Found: C, 61.65; H, 6.67; N, 14.30.
  • Example 367 4-Methoxybenzyl 4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]butane-1-sulfonamide
  • [0986]
    Figure US20040147543A1-20040729-C00433
  • Part A [0987]
  • Over a period of three minutes, p-methoxybenzylamine (1.9 mL, 15 mmol) was added dropwise to a stirred solution of 4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonyl chloride (2.9 g, 6.1 mmol), prepared according to the methods described in Parts A-H of Example 365, in dichloromethane (60 mL). The reaction was stirred at ambient temperature for 90 minutes then diluted with dichloromethane (150 mL) and brine (100 mL). The aqueous layer was separated and extracted with dichloromethane (2×30 mL); the combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with dichloromethane (30 mL) to provide a white solid, which was isolated by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 90:10 to 20:80) to provide a white solid, which was triturated with dichloromethane and isolated by filtration. The solids were combined to yield 1.92 g of 4-methoxybenzyl 4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonamide as a white solid. [0988]
  • Part B [0989]
  • 4-Methoxybenzyl 4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonamide was oxidized and then aminated according to the general method described in Part J of Example 365. The oxidation reaction was stirred for five hours, and the amination reaction was stirred overnight. The crude product was purified twice by column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 95:5 to 80:20) to provide 0.80 g of 4-methoxybenzyl 4-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonamide. This material was mixed with material from another run. [0990]
  • Part C [0991]
  • 4-Methoxybenzyl 4-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonamide (1.16 g, 2.0 mmol) and pyridine-3-boronic acid (0.30 g, 2.4 mmol) were coupled according to the method described in Part J of Example 1. The reaction was heated at reflux for 14 hours, at which time additional pyridine-3-boronic acid (0.3 equivalent) was added and the reaction was heated for an additional five hours. The work-up procedure used in Part F of Examples 125-135 was followed. The crude product was purified by column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 100:0 to 80:20) and then triturated with methanol, isolated by filtration, and dried for 20 hours under high vacuum at 140° C. to provide 0.62 g of 4-methoxybenzyl 4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]butane-1-sulfonamide as a beige powder, mp 230-231.5° C. [0992]
  • Anal. Calcd for C[0993] 30H34N6O4S: C, 62.70; H, 5.96; N, 14.62. Found: C, 62.39; H, 6.06; N, 14.56.
  • Example 368 4-[4-Amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]butane-1-sulfonamide
  • [0994]
    Figure US20040147543A1-20040729-C00434
  • A solution of 4-methoxybenzyl 4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]butane-1-sulfonamide (0.50 g, 0.88 mmol) in trifluoroacetic acid (5 mL) was stirred at ambient temperature for four hours and then concentrated under reduced pressure. The residue was dissolved in methanol and concentrated under reduced pressure; this process was repeated three times. The residue was then suspended in water, and 2 M aqueous sodium hydroxide was added to adjust to pH 7. The mixture was stirred for 30 minutes, and the resulting solid was isolated by filtration, washed with water, and purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 30:70). The purified product was dried overnight under high vacuum at 80° C. to provide 0.31 g of 4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]butane-1-sulfonamide as tan needles, mp 250-251.5° C. [0995]
  • Anal. Calcd for C[0996] 22H26N6O3S: C, 58.13; H, 5.77; N, 18.49. Found: C, 57.89; H, 5.44; N, 18.16.
  • Example 369 Methyl 4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]butane-1-sulfonamide
  • [0997]
    Figure US20040147543A1-20040729-C00435
  • Part A [0998]
  • The method described in Part I of Example 365 was used to treat 4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonyl chloride (1.61 g, 3.49 mmol), prepared according to the methods described in Parts A-H of Example 365, with methylamine hydrochloride (0.50 g, 7.3 mmol) and aqueous potassium carbonate (1.3 mL of 6 M, 7.7 mmol) to provide 1.4 g of methyl 4-[7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl]butane-1-sulfonamide as a tan solid. [0999]
  • Part B [1000]
  • Methyl 4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonamide was oxidized and then aminated according to the general method described in Part J of Example 365. The oxidation reaction was stirred for three hours, and the amination reaction was stirred for 90 minutes. The crude product was recrystallized from a mixture of dichloromethane, heptane, and a trace of methanol and isolated by filtration. The mother liquor was concentrated and purified by column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 95:5 to 80:20) and then triturated with dichloromethane and isolated by filtration. The products were dried overnight under high vacuum at 140° C. to provide a total of 0.86 g of methyl 4-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonamide as a white solid, mp 199-200° C. [1001]
  • Anal. Calcd for C[1002] 18H24BrN5O3S: C, 45.96; H, 5.14; N, 14.89. Found: C, 46.02; H, 4.85; N, 14.65.
  • Part C [1003]
  • Methyl 4-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonamide (0.78 g, 1.7 mmol) and pyridine-3-boronic acid 1,3-propanediol cyclic ester (0.33 g, 2.0 mmol) were coupled according to the method described in Part J of Example 1. The reaction was heated at reflux for 15 hours, at which time additional pyridine-3-boronic acid 1,3-propanediol cyclic ester, palladium acetate, and triphenylphosphine were added, and the reaction was heated for an additional three hours. The work-up procedure used in Part F of Examples 125-135 was followed. The crude product was purified twice by column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 95:5 to 70:30) and then triturated with methanol, isolated by filtration, and dried for eight hours under high vacuum at 100° C. to provide 0.78 g of methyl 4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]butane-1-sulfonamide as off-white needles, mp 216-218° C. [1004]
  • Anal. Calcd for C[1005] 23H28N6O3S.0.23H2O: C, 58.44; H, 6.07; N, 17.78. Found: C, 58.08; H, 5.97; N, 17.71.
  • Example 370 Dimethyl 5-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]pentane-1-sulfonamide
  • [1006]
    Figure US20040147543A1-20040729-C00436
  • Part A [1007]
  • The method described in Part A of Example 365 was used to treat 7-bromo-4-chloro-3-nitroquinoline (20.0 g, 69.5 mmol) with 4-amino-1-pentanol (7.9 g, 76 mmol) to provide 24.0 g of 5-(7-bromo-3-nitroquinolin-4-ylamino)pentan-1-ol as a yellow solid. [1008]
  • Part B [1009]
  • A suspension of 5-(7-bromo-3-nitroquinolin-4-ylamino)pentan-1-ol (0.92 g, 2.6 mmol) in dichloromethane (13 mL) was cooled to 0° C.; thionyl chloride was added dropwise. The reaction was stirred for five minutes at 0° C. then allowed to warm to ambient temperature and stirred overnight. Saturated aqueous sodium bicarbonate (25 mL) was slowly added followed by water (25 mL). The aqueous layer was separated and extracted with dichloromethane (3×50 mL), and the combined organic fractions were dried over magnesium sulfate and concentrated under reduced pressure to provide 0.91 g of (7-bromo-3-nitroquinolin-4-yl)-(5-chloropentyl)amine as a yellow semisolid. [1010]
  • Part C [1011]
  • The methods described in Parts C-E of Example 365 were used to convert (7-bromo-3-nitroquinolin-4-yl)-(5-chloropentyl)amine to 7-bromo-1-(5-chloropentyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline. The crude product was purified twice by column chromatography on silica gel (eluting with chloroform:methanol in a gradient from 100:0 to 90:10). [1012]
  • Part D [1013]
  • Thiourea (0.29 g, 3.8 mmol) and potassium iodide (0.052 g, 3.1 mmol) were sequentially added to a suspension of 7-bromo-1-(5-chloropentyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline (1.3 g, 3.2 mmol) in DMF (15 mL), and the reaction was heated at 110° C. for 24 hours. The DMF was removed under reduced pressure, and the residue was partitioned between saturated aqueous sodium bicarbonate (40 mL) and dichloromethane (50 mL). The mixture was adjusted to pH 7 with the addition of 10% hydrochloric acid. Product remained on the walls of the reaction flask and was dissolved with methanol. The resulting solution was concentrated under reduced pressure to provide a solid. The aqueous layer was concentrated under reduced pressure, and the resulting solid was triturated with methanol and isolated by filtration. The filtrate was concentrated under reduced pressure, and the residue was triturated and isolated as described above. The isolated solids were combined and dried under high vacuum to provide 1.49 g of 2-[5-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentyl]isothiourea hydrochloride as a yellow solid. [1014]
  • Part E [1015]
  • A solution of 2-[5-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentyl]isothiourea hydrochloride (1.49 g, 3.16 mmol) in 7 M hydrochloric acid (8 mL) was cooled to 0° C. A solution of sodium chlorate (0.44 g, 4.1 mmol) in water (1.0 mL) was added dropwise with stirring, and the reaction was stirred at 0° C. for one hour. A precipitate formed and was isolated by filtration, washed with ice-cold water (4×4 mL), and dried under high vacuum to provide 0.92 g of 5-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentane-1-sulfonyl chloride as a yellow solid. [1016]
  • Part F [1017]
  • The method described in Part I of Example 365 was used to treat 5-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentane-1-sulfonyl chloride (0.91 g, 1.9 mmol) with dimethylamine hydrochloride (0.33 g, 4.0 mmol). The crude product was purified by HPFC (eluting with ethyl acetate:methanol in a gradient from 100:0 to 90:10) to provide 0.57 g of dimethyl 5-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentane-1-sulfonamide as a yellow solid. [1018]
  • Part G [1019]
  • Dimethyl 5-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentane-1-sulfonamide was oxidized and aminated according to the methods described in Part J of Example 365. The crude product was purified twice by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 90:10) and then triturated with ethyl acetate, isolated by filtration, washed with ethyl acetate (2×1 mL), and dried for several hours under high vacuum at 150° C. to provide dimethyl 5-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentane-1-sulfonamide as a yellow solid. [1020]
  • Part H [1021]
  • Dimethyl 5-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentane-1-sulfonamide (0.26 g, 0.53 mmol) and pyridine-3-boronic acid (0.78 g, 0.63 mmol) were coupled according to the method described in Part J of Example 1. The reaction was heated at 100° C. for 31 hours, at which time additional palladium acetate (0.002 equivalent) was added. Heating was resumed for 14 hours, and then additional pyridine-3-boronic acid (0.3 equivalent) was added. The reaction was heated for another 22 hours. The work-up procedure used in Part F of Examples 125-135 was followed. The crude product was purified twice by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 80:20) and then triturated with ethyl acetate and isolated by filtration. The product was finally recrystallized from isopropanol, isolated by filtration, and dried for eight hours under high vacuum at 100° C. to provide 0.090 g of dimethyl 5-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]pentane-1-sulfonamide as a white powder, mp 159-160° C. [1022]
  • Anal. Calcd for C[1023] 25H32N6O3S: C, 60.46; H, 6.49; N, 16.92. Found: C, 60.33; H, 6.56; N, 16.81.
  • Example 371 Methyl 5-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]pentane-1-sulfonamide
  • [1024]
    Figure US20040147543A1-20040729-C00437
  • Part A [1025]
  • The method described in Part I of Example 365 was used to treat 5-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentane-1-sulfonyl chloride (1.11 g, 2.33 mmol) with methylamine hydrochloride (0.33 g, 4.9 mmol). The reaction was stirred overnight, and additional methylamine hydrochloride (0.3 equivalent) and 6 M potassium carbonate (0.4 equivalent) were added. The reaction was stirred for an additional four hours. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 80:20) to provide 0.80 g of methyl 5-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentane-1-sulfonamide as a white solid. [1026]
  • Part B [1027]
  • Methyl 5-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentane-1-sulfonamide was oxidized and aminated according to the methods described in Part J of Example 365. The oxidation reaction was stirred for three hours, and the amination reaction was stirred for 90 minutes. The product precipitated from the reaction mixture and was isolated by filtration. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 80:20) to provide methyl 5-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentane-1-sulfonamide as a white solid. [1028]
  • Part C [1029]
  • Methyl 5-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentane-1-sulfonamide (0.47 g, 0.97 mmol) was coupled with pyridine-3-boronic acid (0.14 g, 1.2 mmol) according to the methods described in Part J of Example 1 and Part H of Example 370. The crude product was purified twice by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 70:30) and then recrystallized from methanol, isolated by filtration, and dried for 5 days under high vacuum at 100-140° C. to provide 0.13 g of methyl 5-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]pentane-1-sulfonamide as a white powder, mp 191-192° C. [1030]
  • Anal. Calcd for C[1031] 24H30N6O3S: C, 59.73; H, 6.27; N, 17.41. Found: C, 59.48; H, 6.58; N, 17.56.
  • Examples 372-376
  • Part A [1032]
  • A solution of tert-butyl {4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}carbamate (40.35 g, 82.24 mmol) in concentrated hydrochloric acid (400 mL) was stirred for one hour, filtered, and concentrated under reduced pressure. The residue was dissolved in a minimal amount of water, and 50% aqueous sodium hydroxide was added to adjust the solution to pH 14. Chloroform (1.2 L) and a mixture of saturated aqueous sodium bicarbonate and 1% aqueous sodium carbonate (600 mL) were added; the mixture was stirred for 30 minutes. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure to provide 36.48 g of 1-(4-aminobutyl)-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a light yellow solid. [1033]
  • Part B [1034]
  • Triethylamine (1.39 mL, 10.0 mmol) was added to a solution of 1-(4-aminobutyl)-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (3.00 g, 7.70 mmol) in chloroform (150 mL); the reagent (1.1 equivalents) listed in the table below was then added. The reaction was stirred for one hour or until completion; additional triethylamine and the indicated reagent were added as need until the reaction was complete. Deionized water (15-20 mL) was added, and the mixture was stirred for five minutes. The organic layer was separated, washed with 1% aqueous sodium carbonate, optionally dried with sodium sulfate and filtered, and concentrated under reduced pressure. The crude product was recrystallized from the solvent listed in the table below and dried overnight in a drying oven to provide the compound with the structure shown below. [1035]
    Figure US20040147543A1-20040729-C00438
    Recrystallization
    Example Reagent solvent R
    372 Butyryl chloride Acetonitrile:water 83:17
    Figure US20040147543A1-20040729-C00439
    373 Isobutyryl chloride Isopropanol then acetonitrile:water
    Figure US20040147543A1-20040729-C00440
    374 Cyclopentanecarbonyl chloride Acetonitrile:water, isopropanol, methyl acetate, then isopropanol
    Figure US20040147543A1-20040729-C00441
    375 Methanesulfonic anhydride Precipitated during work-up, no recrystallization done
    Figure US20040147543A1-20040729-C00442
    376 1-Propanesulfonyl chloride Isopropanol then acetonitrile:water 75:25
    Figure US20040147543A1-20040729-C00443
    mp
    Example Name Form (°C.) Anal.
    372 N-{4-[4-Amino-2-ethoxymethyl- 7-(pyridin-3-yl)-1H-imidazo[4,5- c]quinolin-1-yl]butyl}butyramide White soid 150-152 Calcd for C26H32N6O2: C, 67.80; H, 7.00; N, 18.25. Found: C, 67.51; H, 7.29; N, 18.18.
    373 N-{4-[4-Amino-2-ethoxymethyl- 7-(pyridin-3-yl)-1H-imidazo[4,5- c]quinolin-1-yl]butyl}-2- methylpropanamide White solid 200-202 Calcd for C26H32N6O2: C, 67.80; H, 7.00; N, 18.25. Found: C, 67.47; H, 7.09; N, 18.16.
    374 N-{4-[4-Amino-2-ethoxymethyl- 7-(pyridin-3-yl)-1H-imidazo[4,5- c]quinolin-1- yl]butyl}cyclopentanecarboxamide White solid 196-198 Calcd for C28H34N6•O20.25 H2O: C, 68.48; H, 7.08; N, 17.11. Found: C, 68.28; H, 7.36; N, 17.00.
    375 N-{4-[4-Amino-2-ethoxymethyl- 7-(pyridin-3-yl)-1H-imidazo[4,5- c]quinolin-1- yl]butyl}methanesulfonamide White solid 186-188 Calcd for C23H28N6O3S•0.25 H2O: C, 58.39; H, 6.07; N, 17.76. Found: C, 58.31; H, 5.75; N, 17.72.
    376 N-{4-[4-Amino-2-ethoxymethyl- 7-(pyridin-3-yl)-1H-imidazo[4,5- c]quinolin-1-yl]butyl}propane-1- sulfonamide Off- white solid 178-180 Calcd for C25H32N6O3S: C, 60.46; H, 6.49; N, 16.92. Found: C, 60.22; H, 6.42; N, 16.77.
  • Examples 377-379
  • The isocyanate indicated in the table below was added slowly to a solution of 1-(4-aminobutyl)-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (1 equivalent) in chloroform (20-50 mL/g). A precipitate formed within five minutes or formed upon cooling the reaction mixture to ˜0° C. after 15 minutes. The precipitate was isolated by filtration and dried overnight in an oven. The solid was slurried with the solvent(s) listed in the table below, isolated by filtration, and dried overnight in an oven to provide the product with the structure shown in the table below. [1036]
  • Examples 377-379
  • [1037]
    Figure US20040147543A1-20040729-C00444
    Example Isocyanate Purification solvent R
    377 Cyclopentyl isocyante Acetonitrile:water 75:25
    Figure US20040147543A1-20040729-C00445
    378 Propyl isocyanate Not used
    Figure US20040147543A1-20040729-C00446
    379 Isopropyl isocyanate Hot isopropanol
    Figure US20040147543A1-20040729-C00447
    mp
    Example Name Form (° C.) Anal.
    377 N-{4-[4-Amino-2- ethoxymethyl-7-(pyridin- 3-yl)-1H-imidazo[4,5- c]quinolin-1-yl]butyl}-N′- cyclopentylurea White solid 190-192 Calcd for C28H35N7O2: C, 67.04; H, 7.03; N, 19.55. Found: C, 66.76; H, 7.01; N, 19.46.
    378 N-{4-[4-Amino-2- ethoxymethyl-7-(pyridin- 3-yl)-1H-imidazo[4,5- c]quinolin-1-yl]butyl}-N′- propylurea White solid 191-193 Calcd for C26H33N7O2: C, 65.66; H, 6.99; N, 20.62. Found: C, 65.84; H, 7.43; N, 20.66.
    379 N-{4-[4-Amino-2- ethoxymethyl-7-(pyridin- 3-yl)-1H-imidazo[4,5- c]quinolin-1-yl]butyl}-N′- (1-methylethyl)urea White solid 192-194 Calcd for C26H33N7O2: C, 65.66; H, 6.99; N, 20.62. Found: C, 65.83; H, 7.39; N, 20.52.
  • Examples 380-382
  • A solution of tert-butyl {4-[4-amino-2-propyl-7-(pyridin-3-yl)-1H-imidazol[4,5-c]quinolin-1-yl]butyl}carbamate (41.92 g, 88.32 mmol) in concentrated hydrochloric acid (210 mL) was stirred for ten minutes, and 50% aqueous sodium hydroxide was added to adjust the solution to pH 14. Cloroform (2.0 L) and a mixture of saturated aqueous sodium bicarbonate and 1% aqueous sodium carbonate (300 mL) were added. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure to provide a yellow solid. The aqueous phase was treated with sodium chloride and chloroform (400 mL), and the mixture was stirred overnight. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure to provide a yellow solid. The two solids were combined to yield 28.77 g of 1-(4-aminobutyl)-2-propyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a light yellow solid. [1038]
  • Triethylamine (1.34 mL, 9.61 mmol) was added to a solution of 1-(4-aminobutyl)-2-propyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (3.00 g, 8.01 mmol) in chloroform (141 mL); the solution was then cooled to 0° C. A cold solution of the reagent (1.0 equivalent) listed in the table below in chloroform (9 mL) was then added. The reaction was stirred for 15 or 90 minutes, and deionized water (25 mL) was added. A precipitate formed and was isolated by filtration and dried overnight in a drying oven. The crude product was triturated with the solvent(s) listed in the table below, isolated by filtration, and dried overnight in a drying oven to provide the compound with the structure shown below. [1039]
  • Examples 380-382
  • [1040]
    Figure US20040147543A1-20040729-C00448
    Example Reagent Purification solvent R
    380 Butyryl chloride Chloroform (10 mL/g) and 1% aqueous sodium carbonate (3 mL/g)
    Figure US20040147543A1-20040729-C00449
    381 Isobutyryl chloride Not used
    Figure US20040147543A1-20040729-C00450
    382 Cyclopentanecarbonyl chloride Chloroform (10 mL/g) then recrystallized from isopropanol (6 mL/g)
    Figure US20040147543A1-20040729-C00451
    mp
    Example Name Form (° C.) Anal.
    380 N-{4-[4-Amino-2-propyl-7- (pyridin-3-yl)-1H-imidazo[4,5- c]quinolin-1-yl]butyl}butyramide White solid 144-146 Calcd for C26H32N6O•2 H2O: C, 64.98; H, 7.55; N, 17.49. Found: C, 64.53; H, 7.08; N, 17.44.
    381 N-{4-[4-Amino-2-propyl-7- (pyridin-3-yl)-1H-imidazo[4,5- c]quinolin-1-yl]butyl}-2- methylpropanamide White solid 168-170 Calcd for C26H32N6O•0.25 H2O: C, 69.54; H, 7.29; N, 18.71. Found: C, 69.45; H, 7.67; N, 18.65.
    382 N-{4-[4-Amino-2-propyl-7- (pyridin-3-yl)-1H-imidazo[4,5- c]quinolin-1- yl]butyl}cyclopentanecarboxamide White solid 180-182 Calcd for C28H34N6O•1.5 H2O: C, 67.58; H, 7.49; N, 16.89. Found: C, 67.51; H, 7.72; N, 17.09.
  • Examples 383-385
  • A solution of 1-(4-aminobutyl)-2-propyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (1 equivalent) in chloroform (18 mL/g) was cooled to 0° C.; a cold solution of the isocyanate indicated in the table below (1.05 equivalents) in chloroform (2 mL/g) was added. A precipitate formed within ten minutes or formed upon cooling the reaction mixture to ˜0° C. for 30 minutes. The precipitate was isolated by filtration and dried overnight in an oven. The solid was from 1:1 acetonitrile:water, isolated by filtration, and dried for five days in an oven at 63° C. to provide the product with the structure shown in the table below. [1041]
  • Examples 383-385
  • [1042]
    Figure US20040147543A1-20040729-C00452
    Example Isocyanate R
    383 Cyclopentyl isocyanate
    Figure US20040147543A1-20040729-C00453
    384 Propyl isocyanate
    Figure US20040147543A1-20040729-C00454
    385 Isopropyl isocyanate
    Figure US20040147543A1-20040729-C00455
    mp
    Example Name Form (° C.) Anal.
    383 N-{4-[4-Amino-2-propyl- 7-(pyridin-3-yl)-1H- imidazo[4,5-c]quinolin-1- yl]butyl}-N′- cyclopentylurea White solid 181-183 Calcd for C28H35N7O•1.5 H2O: C, 65.60; H, 7.47; N, 19.13. Found: C, 65.44; H, 7.61; N, 19.09.
    384 N-{4-[4-Amino-2-propyl- 7-(pyridin-3-yl)-1H- imidazo[4,5-c]quinolin-1- yl]butyl}-N′-propylurea White solid 184-185 Calcd for C26H33N7O•0.25 H2O: C, 67.29; H, 7.28; N, 21.13. Found: C, 67.15; H, 7.56; N, 21.41.
    385 N-{4-[4-Amino-2-propyl- 7-(pyridin-3-yl)-1H- imidazo[4,5-c]quinolin-1- yl]butyl}-N′-(1- methylethyl)urea White solid 173-175 Calcd for C26H33N7O•1.25 H2O: C, 64.77; H, 7.42; N, 20.34. Found: C, 64.36; H, 7.78; N, 20.21.
  • Example 386 N-{2-[4-Amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}-2-methylpropanamide
  • [1043]
    Figure US20040147543A1-20040729-C00456
  • Part A [1044]
  • A solution of 7-bromo-4-chloro-3-nitroquinoline (140.00 g, 486.96 mmol) in chloroform (2.8 L) was cooled to 0° C. Triethylamine (82.0 mL, 588 mol) and ethylenediamine (35.75 mL, 535.6 rnrnol) were sequentially added; the resulting mixture was stirred for one hour at 0° C. then allowed to warm to ambient temperature and stirred for two hours. Additional ethylenediamine (0.1 equivalent) was added, and the reaction was stirred for an additional 1.75 hours. Additional triethylamine (88.0 mL, 631 mmol) followed by a solution of di-tert-butyl dicarbonate (180.0 mL, 779.1 mmol) in chloroform (320 mL) were added, and the reaction was stirred overnight at ambient temperature. Water (750 mL) was added, and the mixture was stirred for 15 minutes. The organic layer was separated and washed with 1% aqueous sodium carbonate (2×750 mL), dried over sodium sulfate, filtered through a layer of CELITE filter aid, and concentrated under reduced pressure. The resulting solid was triturated with hot acetonitrile (5 mL/g at 95° C.), cooled in an ice bath, and isolated by filtration to provide 165.0 g of tert-butyl [2-(7-bromo-3-nitroquinolin-4-ylamino)ethyl]carbamate as a light yellow solid. [1045]
  • Part B [1046]
  • A solution of tert-butyl [2-(7-bromo-3-nitroquinolin-4-ylamino)ethyl]carbamate (165.0 g, 401.2 mmol) in acetonitrile (3.3 L) and, isopropanol (990 mL) and 5% platinum on carbon (13.2 g) were added to a Parr vessel, which was placed under hydrogen pressure (50 psi, 3.4×105 Pa) overnight. The mixture was filtered through a layer of CELITE filter aid, and the filtrate was concentrated under reduced pressure to provide 139.29 g of tert-butyl [2-(3-amino-7-bromoquinolin-4-ylamino)ethyl]carbamate as a yellow solid. The product was suspended in a mixture of dichloromethane (4 mL/g) and chloroform (8 mL/g), and the suspension was divided into two equal portions. [1047]
  • Part C [1048]
  • Ethoxyacetyl chloride (25.44 g, 182.7 mmol) in chloroform (50 mL) was added to one portion of the suspension from Part B. The resulting brown solution was stirred for 30 minutes and then concentrated under reduced pressure. [1049]
  • Part D [1050]
  • Triethylamine (101.85 mL, 730.7 mmol) was added to a suspension of the material from Part C in ethanol (1.1 L); the mixture was heated at reflux for two hours, allowed to stand over three days, and concentrated under reduced pressure. The residue was partitioned between chloroform (1.2 L) and water (400 mL). The organic layer was separated, washed with brine (2×400 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was triturated with acetonitrile (10 mL/g) at 95° C., isolated by filtration, and dried for three days to provide 51.48 g of tert-butyl [2-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate as a white solid. [1051]
  • Part E [1052]
  • A modification of the method described in Example 1 Part H was used to oxidize tert-butyl [2-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate (36.48 g, 81.18 mmol) with 3-chloroperoxybenzoic acid (36.31 g of 77% pure material, 105.5 mmol). The reaction was carried out in chloroform (370 mL) and allowed to proceed for 30 minutes. The crude product was used without purification. [1053]
  • Part F [1054]
  • The material from Part E was aminated according to the method described in Part I of Example 1; the reaction was complete after one hour. The crude product was triturated with acetonitrile (7 mL/g) at 95° C., and the resulting solid was isolated by filtration to provide 26.89 g of tert-butyl [2-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate as a fluffy, white solid. [1055]
  • Part G [1056]
  • tert-Butyl [2-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate (21.80 g, 46.94 mmol) and 3-pyridylboronic acid (6.64 g, 54.0 mrnmol) were coupled according to the method described in Part J of Example 1. Palladium (II) acetate was added as a 5 mg/mL solution in toluene. The reaction was terminated after 4.5 hours, and the work-up procedure described in Part F of Examples 125-135 was followed. The crude product was recrystallized from acetonitrile (12 mUg) to provide 10.80 g of tert-butyl {2-[2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}carbamate as a white solid. [1057]
  • Part H [1058]
  • The method described in Part A of Examples 372-376 was used to convert tert-butyl {2-[2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}carbamate (10.80 g, 23.34 mmol) to 8.38 g of 1-(2-aminoethyl)-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid. [1059]
  • Part I [1060]
  • 1-(2-Aminoethyl)-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 5.50 mmol) was treated with triethylamine (1.00 mL, 7.20 mmol) and isobutyryl chloride (0.64 mL, 6.10 mmol) according to the method described in Part B of Examples 372-376. The crude product was recrystallized from 93:7 acetonitrile:water and then from isopropanol (7.3 mL/g) and dried for two hours in a drying oven to provide 0.78 g of N-{2-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}-2-methylpropanamide as a white solid, mp 213-215° C. [1061]
  • Anal. Calcd for C[1062] 24H28N6O2.0.75H2O: C, 64.63; H, 6.67; N, 18.84. Found: C, 64.66; H, 6.54; N, 18.71.
  • Example 387 N-{2-[4-Amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}methanesulfonamide
  • [1063]
    Figure US20040147543A1-20040729-C00457
  • A solution of 1-(2-aminoethyl)-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 5.50 mmol) in chloroform (40 mL) was treated with triethylamine (1.62 mL, 11.6 mmol) and methanesulfonyl chloride (0.47 mL, 6.05 mmol). The reaction was stirred for 1.5 hours, and additional methanesulfonyl chloride (2 equivalents) was added. The reaction was stirred for 30 minutes, and then deionized water (15 mL) was added. A precipitate formed and was isolated by filtration, triturated once with methanol and twice with chloroform and 1% aqueous sodium carbonate, isolated by filtration, and dried overnight in an oven to provide 0.65 g of N-{2-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}methanesulfonamide as a white solid, mp 233-235° C. [1064]
  • Anal. Calcd for C[1065] 21H24N6O3S.0.5H2O: C, 56.1 1; H, 5.61; N, 18.69. Found: C,
  • Anal. Calcd for C[1066] 21H24N6O3S.0.5H2O: C, 56.1 1; H, 5.61; N, 18.69. Found: C,
  • Example 388 N-{2-[4-Amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}-N′-(1-methylethyl)urea
  • [1067]
    Figure US20040147543A1-20040729-C00458
  • A solution of 1-(2-aminoethyl)-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (2.50 g, 6.90 mmol) in chloroform (50 mL) was treated with isopropyl isocyanate (0.65 mL, 6.9 mmol) according to the method described in Examples 377-379. The crude product was purified by column chromatography on silica gel (eluting with 94:6 chloroform:methanol) followed by trituration with acetonitrile (15 mL/g) at 95° C. The mixture was cooled in an ice bath, isolated by filtration, and dried for one hour in a vacuum oven at 100° C. to provide 0.88 g of N-{2-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}-N′-(1-methylethyl)urea as a white solid, mp 194-196° C. [1068]
  • Anal. Calcd for C[1069] 24H29N7O2: C, 64.41; H, 6.53; N, 21.91. Found: C, 64.34; H, 6.82; N, 22.05.
  • Example 389 1-[2-(1,1-Dioxo-1-isothiazolidin-2-yl)ethyl]-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine
  • [1070]
    Figure US20040147543A1-20040729-C00459
  • 3-Chloropropanesulfonyl chloride (2.52 mL, 20.7 mmol) was added to a solution of 1-(2-aminoethyl)-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (2.50 g, 6.90 mmol) in chloroform (50 mL) in two portions over a period of two hours, and the reaction was stirred overnight at ambient temperature. Additional 3-chloropropanesulfonyl chloride (1.72 mL, 14.1 mmol) was added followed by triethylamine (2.02 mL, 14.9 mmol) to drive the reaction to completion. Chloroform (50 mL) and water (30 mL) were added, and the mixture was stirred for five minutes. A precipitate formed, was isolated by filtration, and was mixed with DMF (66 mL) and DBU (2.06 mL, 13.8 mmol). The resulting solution was stirred for three days at ambient temperature and then combined with water (660 mL) and chloroform (400 mL). The organic layer was separated and dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 95:5 chloroform:methanol). The resulting solid was triturated with methanol at 80° C., cooled in an ice bath, isolated by filtration, and dried overnight in a vacuum oven to provide 0.28 g of 1-[2-(1,1-dioxo-1-isothiazolidin-2-yl)ethyl]-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 244-246° C. [1071]
  • Anal. Calcd for C[1072] 23H26N6O3S.0.11H2O: C, 58.96; H, 5.64; N, 17.94. Found: C, 58.86; H, 5.69; N, 17.90.
  • Example 390 N-{2-[4-Amino-2-butyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}-2-methylpropanamide
  • [1073]
    Figure US20040147543A1-20040729-C00460
  • Part A [1074]
  • Valeryl chloride (21.68 mL, 182.6 mmol) in chloroform (50 mL) was added to one portion of the suspension from Part B of Example 386. The resulting brown solution was stirred for 30 minutes and then concentrated under reduced pressure. [1075]
  • Part B [1076]
  • A solution of sodium hydroxide (21.92 g, 274.0 mmol) in water (110 mL) was added to a suspension of the material from Part A in ethanol (640 mL); the mixture was heated at reflux for four hours and then concentrated under reduced pressure. The residue was partitioned between chloroform (1.2 L) and deionized water (400 mL). The mixture was stirred for 30 minutes. The organic fraction was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was triturated with isopropanol at 95° C., isolated by filtration, and dried on the filter funnel to provide 39.78 g of tert-butyl [2-(7-bromo-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate as a pinkish-gray solid. [1077]
  • Part C [1078]
  • tert-Butyl [2-(7-bromo-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate (24.78 g, 55.4 mmol) was oxidized and then aminated according to the methods described in Parts E and F of Example 386. After purification 19.13 g of tert-butyl [2-(4-amino-7-bromo-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate was obtained as a gray solid. [1079]
  • Part D [1080]
  • tert-Butyl [2-(4-amino-7-bromo-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate (14.09 g, 30.5 mmol) and 3-pyridylboronic acid (4.31 g, 35.0 mmol) were coupled according to the method described in Part G of Example 386. The reaction was heated for 2.5 hours. The crude product was triturated with toluene (15 mL/g) at 123° C. and isolated by filtration to provide 11.31 g of tert-butyl {2-[2-butyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}carbamate as a white solid. [1081]
  • Part E [1082]
  • The method described in Part A of Examples 372-376 was used to convert tert-butyl {2-[2-butyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}carbamate (11.31 g, 24.56 mmol) to 1-(2-aminoethyl)-2-butyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine. [1083]
  • Part F [1084]
  • 1-(2-Aminoethyl)-2-butyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 5.50 mmol) was treated with triethylamine (1.01 mL, 7.26 mmol) and isobutyryl chloride (0.64 mL, 6.10 mmol) according to the method described in Part B of Examples 372-376. The crude product was recrystallized from isopropanol (4 mL/g) and then triturated with acetonitrile (12.5 mL/g), isolated by filtration, and dried overnight in a drying oven to provide 0.61 g of N-{2-[4-amino-2-butyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}-2-methylpropanamide as a white solid, mp 228-230° C. [1085]
  • Anal. Calcd for C[1086] 25H30N6O: C, 69.74; H, 7.02; N, 19.52. Found: C, 69.37; H, 6.97; N, 19.60.
  • Example 391 N-{2-[4-Amino-2-butyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}methanesulfonamide
  • [1087]
    Figure US20040147543A1-20040729-C00461
  • The method described in Example 387 was used to convert 1-(2-aminoethyl)-2-butyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine to N-{2-[4-amino-2-butyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}methanesulfonamide. [1088]
  • Example 392 N-{2-[4-Amino-2-butyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}-N′-(1-methylethyl)urea